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Nathan Goodyear

Biological functions and clinical implications of oestrogen receptors alfa and beta in ... - 0 views

onlinelibrary.wiley.com/...full

ER estrogen receptors ER-alpha ER alpha ER-beta ER beta hormones hormone

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • ERα-positive cells respond to E2 with increased proliferation
  • ERβ was artificially introduced into these cells, E2-induced proliferation was inhibited
  • The proliferative response to E2 seems to be determined by the ratio of ERα/ERβ. The functions of ERβ in the breast are probably related to its antiproliferative as well as its prodifferentiative functions
  • ...7 more annotations...
  • The risk of developing PC seems to be related to the diet
  • In the human prostate, ERβ is expressed in the basal epithelial cells and AR in the luminal epithelium.
  • For many years, DHT was considered to be the main hormone guiding prostate development and function. However, the idea was challenged when in 2001 Mahendroo et al. showed that mice in which both forms of 5α-reductase had been inactivated, have a normal functional prostate [50]. The question was then raised as to what is the real function of DHT in the prostate. In 1989 we hypothesized that DHT is a precursor of an oestrogen, 5α-androstane-3β,17β-diol (3β-Adiol) and that physiological levels of an oestrogen could be produced in the total absence of aromatase [51]. We later demonstrated that 3β-Adiol is abundant in the prostate and is a good natural ligand for ERβ
  • The overall effect of oestrogens in the immune system is determined by a balance between ERα and ERβ signalling
  • The hypothesis of our group is that ERβ plays an important role in regulating the differentiation of pluripotent haematopoietic progenitor cells whereas ERα induces proliferation
  • In tissues and cell lines of mammary epithelium for example, it has been noticed that E2 in the presence of ERα elicits proliferation, but in the presence of ERβ it inhibits proliferation
  • ERα and ERβ have distinctive tissue distributions and to the great surprise of endocrinologists [7] many tissues previously thought to be ‘oestrogen-insensitive tissues’ were found to be ERβ positive and oestrogen sensitive. The most notable of the ERα-negative ERβ-abundant tissues were the epithelium of the rodent ventral prostate [8], the granulosa cells of the ovaries [9] and the parenchyma of the lungs
  • Nathan Goodyear on 21 Jan 14
     
    Awesome article discusses the different balance of ER alpha and ER beta and the effects on tissue as it relates to proliferation versus differentiation.  This has clear implications in disease.  Physicians prescribing hormones without a knowledge and understanding of this are only causing potential harm to their clients.
Nathan Goodyear

Progesterone metabolites in breast cancer - 1 views

erc.endocrinology-journals.org/...717.full

progesterone metabolism tumor tumorigenesis cancer risk growth hormone hormones 5-beta-pregnanediol 5-alpha-pregnanediol 4-pregnenediol 5-alpha reductase

shared by Nathan Goodyear on 20 Feb 12 - No Cached
  • P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
  • these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
  • only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
  • ...30 more annotations...
  • P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
  • 5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
  • These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
  • Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
  • The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
  • the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
  • In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
  • The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
  • he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
  • The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
  • altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
  • In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
  • Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
  • The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
  • 3αHP inhibited whereas 5αP-stimulated proliferation
  • Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
  • Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
  • αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
  • The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
  • he effects on proliferation and adhesion were not due to P, but due to the 5α-reduced metabolites
  • The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
  • separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
  • The studies thus provided the first demonstration of the existence of specific P metabolite receptors
  • the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
  • Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
  • In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
  • The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
  • current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
  • both testosterone and DHT inhibit cell growth more or less to the same extent
  • Note that 5α-reductase reaction is not reversible
  • Nathan Goodyear on 20 Feb 12
     
    Fantastic read on the effects of progesterone metabolism on tumor and cancer growth.  Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones.  This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
Nathan Goodyear

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and p... - 0 views

www.ncbi.nlm.nih.gov/...PMC3706910

progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
  • Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
  • When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
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  • Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
  • Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
  • The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
  • hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
  • a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
  • about 90% of normal proliferating breast epithelial cells are receptor negative
  • Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
  • The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
  • In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
  • the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
  • Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
  • The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
  • The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
  • In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
  • When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
  • The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
  • Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
  • ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
  • 3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
  • serum from mice with tumors had significantly more 5αP than 3αHP
  • the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and >10-fold higher 5αP than 3αHP levels
  • Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
  • Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
  • breast carcinomas are able to synthesize progesterone
  • The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
  • Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
  • 5α-reductase and 5αPR levels are upregulated by 5αP
  • in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
  • the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
  • because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
  • The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites and breast cancer
Nathan Goodyear

Influence of Sex Hormones on Melanoma - 0 views

jco.ascopubs.org/...e94.short

cancer melanoma ER alpha ER-alpha ER beta ER-beta ER estrogen receptor hormones hormone

shared by Nathan Goodyear on 21 Oct 14 - No Cached
  • Men show lower skin levels of ERβ than women, in whom ERβ expression decreases with age and more rapidly after menopause as a result of loss of estradiol-positive feedback
  • lower ERβ (mRNA and protein) levels in thicker, more invasive melanomas
  • melanoma ERβ levels correlated with both the tumor microenvironment and the depth of invasion
  • ...3 more annotations...
  • Recent immunohistochemical analyses of ERβ protein level in melanoma tissues15,16 have shown that ERβ protein expression decreases with increasing Breslow thickness—the most important independent prognostic factor in melanoma.
  • As in breast cancer, we maintain that ERα and ERβ status also has to be determined in melanoma with the aim of identifying those displaying a high ERα/ERβ ratio
  • An ideal hormone therapy in melanoma should selectively block the proliferative ERα protein and promote the antiproliferative action of ERβ
  • Nathan Goodyear on 21 Oct 14
     
    Melanoma is a known estrogen sensitive cancer.  This study finds ER Beta loss correlates with thickness of lesion.  The authors propose ERalpha/ERbeta ratio be assessed.  ERbeta has been shown to decrease proliferation, promotes differentiation, and decrease inflammation in breast studies.  In contrast, ERalpha promotes proliferation, decreases differentiation, and promotes inflammation.  Here, the same effects seem to apply to melanoma. Of interesting note, men have lower skin ERbeta than women and ERbeta declines with age and menopause in women.  Essentially, the loss of the ability to differentiate, decrease proliferation and inflammation  occurs with increase estrogen stimulus--set up for estrogen promoting cancers.
Nathan Goodyear

Evaluation of FLT-PET-CT as an imaging biomarker of proliferation in primary breast can... - 0 views

www.nature.com/...bjc2014207

PET scan PET_CT scan cancer breast

shared by Nathan Goodyear on 19 Mar 18 - No Cached
  • We have demonstrated that the majority of patients have a sizeable reduction in SUVmax from a single cycle of NAC with a mean change of −32.3%
  • This study, however, failed to show any predictive markers of response after one cycle of chemotherapy
  • These data therefore suggest that the main utility of FLT-PET as an imaging biomarker in early breast cancer is pre-chemotherapy, as a marker of proliferation, rather than in predicting pathological response after chemotherapy
  • ...2 more annotations...
  • In terms of the histological proliferation biomarker Ki-67, we have shown a good correlation with FLT-PET pre-chemotherapy. The best predictive marker of response in terms of pCR was baseline Ki-67
  • Our study has shown that baseline Ki-67 and FLT SUVmax is well correlated in keeping with FLT-PETs status as a proliferation biomarker, although Ki-67 had a better predictive ability in terms of pathological outcome
  • Nathan Goodyear on 19 Mar 18
     
    PET CT scan shown to be useful as a proliferation biomarker pre-chemo in breast cancer.
Nathan Goodyear

Natural Killer Cells in Pregnancy and Recurrent Pregnancy Loss: Endocrine and Immunolog... - 0 views

edrv.endojournals.org/...44.full

natural killer cells pregnancy loss recurrent immune system miscarriage NK

shared by Nathan Goodyear on 15 Apr 12 - No Cached
  • NK cells have been the cells most extensively studied, primarily because they constitute the predominant leukocyte population present in the endometrium at the time of implantation and in early pregnancy
  • parental chromosomal abnormalities, uterine anatomic anomalies, endometrial infections, endocrine etiologies (luteal phase defect, thyroid dysfunction, uncontrolled diabetes mellitus), antiphospholipid syndrome, inherited thrombophilias, and alloimmune causes
  • estrogen
  • ...28 more annotations...
  • progesterone
  • prolactin
  • In summary, in vivo animal experiments have shown an inhibitory role of estrogen on peripheral NK cell lytic activity, which is partly due to suppression of NK cell output by the bone marrow and partly due to suppression of individual NK cell cytotoxicity. However, in vitro studies so far have failed to show conclusively a direct effect of estrogen on NK cells.
  • At the progesterone concentrations believed to be present in the uterus [up to 10−5 m at the maternal-fetal interface (35)], studies consistently show inhibition of lymphocyte proliferation (33) and inhibition of NK cytolytic activity in vitro
  • The exact role of prolactin in NK cell regulation is unknown.
  • The overall effects of estrogen on NK cells are likely multifactorial, therefore, and depend on the type of cell affected as well as the kind of ER expressed by that cell.
  • It is known that progesterone can directly affect T cell differentiation in vitro, suppressing development of the Th1 pathway and enhancing differentiation along the Th2 pathway (44)
  • Th1 cells predominantly produce interferon-γ (IFN-γ), IL-2, and TNF-β and are involved in cell-mediated immunity. Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13 and stimulate humoral immunity
  • Furthermore, in response to progesterone, γδ T cells produce progesterone-induced blocking factor (PIBF) (54
  • A defining characteristic of NK cells is their ability to lyse target cells without prior sensitization and without restriction by HLA antigens.
  • NK cell function is mainly regulated by IL-2 and IFN-γ
  • IL-2 causes both NK cell proliferation and enhanced cytotoxicity. IFN-γ augments NK cytolytic activity, but does not cause NK proliferation. The two cytokines act synergistically to augment NK cytotoxicity (6).
  • The largest leukocyte population in the endometrium consists of NK cells named large granulated lymphocytes
  • there is a significant increase in the number of uNK cells throughout the secretory phase, which peaks in early pregnancy when uNK cells comprise about 75% of uterine leukocytes (62)
  • Second, uNK cell phenotype changes during the normal menstrual cycle and early pregnancy (68)
  • general proinflammatory effect of estrogen, causing an influx of macrophages and neutrophils, which is antagonized by progesterone through its receptor (70, 71).
  • The mechanism of such a progesterone-induced local immunosuppression is unclear.
  • progesterone plays an important role in proliferation and differentiation of uNK cells (32).
  • Through promotion of a uterine Th2 environment, progesterone could indirectly affect uNK cell function
  • The mechanism of this increase in uNK cell numbers has been addressed in both human and mouse models, and is likely the result of: 1) recruitment of peripheral NK cells to the uterus, and 2) proliferation of existing uNK cells
  • prolactin system plays an important role in implantation and the maintenance of pregnancy
  • the exact pathways of hormonal regulation of NK cells remain to be delineated.
  • The exact function of uNK cells has not yet been unequivocally determined
  • uNK cells express a different cytokine profile, compared with resting peripheral NK cells. mRNAs for granulocyte CSF, M-CSF, GM-CSF, TNF-α, IFN-γ, TGF-β, and leukemia inhibitory factor (LIF) have been found in decidual CD56+ cells
  • Their increased numbers in early pregnancy, their hormonal dependence, and their close proximity to the infiltrating trophoblast all suggest that they play an important role in the regulation of the maternal immune response to the fetal allograft and the control of trophoblast growth and invasion during human pregnancy
  • role of uNK cell-derived cytokines on trophoblast growth and differentiation (114, 115, 116, 117).
  • Th1 immunity to trophoblast is associated with RPL, whereas Th2 immunity is associated with a successful pregnancy
  • RPL is associated with Th1 immunity, for which NK cells are partly responsible.
  • Nathan Goodyear on 15 Apr 12
     
    dysregulated immune system plays role in recurrent miscarriage.  Specifically, this article discusses natural killer cells (NK).
Nathan Goodyear

The role of androst-5-ene-3β,17β-diol (androstenedi... [Steroids. 2014] - Pub... - 0 views

www.ncbi.nlm.nih.gov/...25065586

DHT metabolite 3-beta androstanediol 3-beta-diol 3 beta androstanediol PCOS endometrial proliferation cancer women hormone hormones Testosterone

shared by Nathan Goodyear on 30 Jul 14 - No Cached
  • Nathan Goodyear on 30 Jul 14
     
    The DHT metabolite 3beta-androstanediol found to increase proliferation of endometrial tissue in women with PCOS.  In contrast, Testosterone repressed proliferation.  
Nathan Goodyear

Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignan... - 0 views

www.ncbi.nlm.nih.gov/...PMC3665464

TK-1 TK-1 cancer thymidine kinase 1 cancer biomarker

shared by Nathan Goodyear on 04 Mar 15 - No Cached
  • Thymidine kinase 1 (TK1) is a proliferation biomarker
  • Nuclear TK1 expression in early grade CIN predicts risk for progression to malignancy
  • Nuclear TK1 expression is also a prognostic factor for treatment outcome
  • ...9 more annotations...
  • TK1 LI was found to be a more reliable prognostic marker for 5-year survival than pathological stages, FIGO stages and Ki-67,
  • nuclear TK1 expression is a reliable prognostic factor in CIN patients, a group of cervical lesion patients that respond positively to treatment
  • nuclear TK1 expression is correlated with advanced stage of invasive cervical carcinomas
  • a low TK1 LI can help to identify with a better survival
  • low TK1 expression in the tumors in these patients might indicate that these tumors have a lower proliferation rate
  • TK1 is a key kinase in the one-step salvage pathway by which thymidine is introduced into DNA via the salvage pathway
  • TK1 participates in DNA synthesis and is therefore closely related to the S-phase of the cell cycle, and is correlated with proliferation
  • TK1 intensity (TK1 synthesis rate) increases from CIN grade I to CIN grade III, but does not further increase in invasive cervical carcinomas.
  • TK1 intensity seems to be a prognostic factor particularly when pre-malignant cervical lesions progress to malignancy
  • Nathan Goodyear on 04 Mar 15
     
    TK-1 is a proliferation biomarker of DNA repair. TK-1 is a nuclear biomarker of cancer prognosis, survival, recurrence and predicts risk of progression of pre-malignant disease.
Nathan Goodyear

Oxidative Stress and Its Relationship With Adenosine Deaminase Activity in Various Stag... - 0 views

www.ncbi.nlm.nih.gov/...PMC3547448

Adenosine Deaminase ADA cancer breast cancer superoxide disumutase glutathione peroxidase oxidative stress inflammation

shared by Nathan Goodyear on 10 Nov 14 - No Cached
  • Reduced SOD activity might be responsible for excessive accumulation of superoxide anions leading to increased free radical mediated injury. Increased free radical production has been shown to be responsible for chromosomal damage leading to mutagenecity, cell proliferation and carcinogenesis. SOD activity showed marked improvement after mastectomy indicating the lowering of oxidative stress.
  • The increased production of reactive oxygen species causes oxidative stress leading to cell proliferation and hence increased inflammatory conditions
  • Superoxide dismutase is an important antioxidant enzyme which decomposes the harmful superoxide anions into hydrogen peroxide thus protects the body from the action of free radicals
  • ...20 more annotations...
  • Females suffering from breast cancer had significantly decreased Superoxide dismutase (SOD) and reduced glutathione (GSH) levels in comparison to normal females
  • ADA seems to be a promising marker of inflammation in breast cancer thereby suggesting that it can be used as a diagnostic tool to detect the stage of breast cancer along with cytopathological studies
  • In conclusion, our study confirmed the role of oxidative stress in the pathogenesis of breast cancer.
  • Another potent antioxidant molecule is reduced glutathione. It acts as reductant which converts hydrogen peroxide into water and reduces lipid peroxidation products into their corresponding alcohols and thus mediates protective action.
  • In the present study, significantly low SOD activity has been observed in female patients suffering from carcinoma breast both pre as well as post operative in comparison to healthy females.
  • We observed significantly decreased SOD activity and GSH levels in patients belonging to clinical stage 4 as compared to those having stages 1, 2 or 3 of breast cancer.
  • Increased ADA activity in breast cancer patients has also been reported
  • The compromised antioxidant defence system produces the oxidative stress which in turn creates the inflammatory response shown by concomitant increased adenosine deaminase (ADA) activity in female patients.
  • Experimental and epidemiological evidences implicate the involvement of oxygen derived free radical in the pathogenesis of breast cancer.
  • Antioxidant status was highly depressed in advanced stages of breast cancer as compared to initial stage.
  • In the present study, significantly low GSH levels were observed in female patients of carcinoma breast as compared to normal females
  • Walia et al. (1995) reported increased ADA activity in breast cancer patients as compared to age matched normal subjects.
  • These free radicals are able to cause damage to membrane, mitochondria and macromolecules including proteins, lipids and DNA and actively take part in cell proliferation. This cascade in turn generates the inflammatory response and causes the progression of the disease.
  • increased oxidative stress gives rise to inflammation which could further aggravates the disease
  • Breast carcinoma involves a cascade of events that are highly inflammatory.
  • Marked oxidative stress in stage 4 of breast cancer indicated advancement of the disease, hence checking oxidative stress at initial stage could be helpful for controlling the progression of the disease.
  • They concluded that ADA is a better probable parameter for detection of breast cancer
  • Adenosine deaminase enzyme (ADA) catalyzes the conversion of adenosine to inosine which finally gets converted to uric acid
  • serum ADA activity tends to increase with advancing age,
  • Prevalence of oxidative stress gives rise to inflammation.
  • Nathan Goodyear on 10 Nov 14
     
    Study finds a reduction in SuperOxide Dismutase and Glutathione Perioxidase in advancing breast cancer.  Cancer is a high oxidative stress disease that results in inflammation, mitochondrial dysfunction and proliferation.  Adenosine Deaminase (ADA) is proposed to be another biomarker to assess tumor stage.  
Nathan Goodyear

Ki-67 is a prognostic parameter in breast cancer patients: results of a large populatio... - 0 views

www.ncbi.nlm.nih.gov/...PMC3669503

ki-67 cancer breast cancer

shared by Nathan Goodyear on 06 Sep 18 - No Cached
  • A wide range of techniques is available to assess tumor cell proliferation such as calculating mitotic figures in stained tissue segments, flow cytometric analysis to determine the proportion of cells being in the S phase of the cell cycle, examination of thymidine-labeling index, proliferating cell nuclear antigen (PCNA), or cyclins E and D
  • Ki-67 is a nuclear protein being associated with cellular proliferation and was originally identified by Gerdes et al.
  • Ki-67 nuclear antigen is expressed in certain phases of the cell cycle namely S, G1, G2, and M phases, but is nonexisting in G0
  • ...11 more annotations...
  • Ki-67 is also expressed at low levels (<3 % of cells) in ER-negative cells, but not in ER-positive cells
  • A meta-analysis involving 12,155 patients demonstrated that the Ki-67 positivity confers a higher risk of recurrence and a worse survival rate in patients with early breast cancer.
  • high levels of Ki-67 are associated with worse prognoses
  • Ki-67 was associated with worse survival rates
  • associated with proliferation
  • higher tumor stages and higher nodal status were associated with higher Ki-67 quartiles indicating that the more aggressive the tumor is the higher is the percentage of cells positively stained for Ki-67
  • Previous studies were able to demonstrate that a prognostic model, the IHC 4 score, using ER, PR, HER2, and Ki-67 provides similar prognostic information to that in the 21-gene Genomic Health recurrence score
  • ER status has been largely identified as being inversely correlated with Ki-67, with the higher rates of ER positivity shown in the lowest proliferating tumors
  • high levels of Ki-67 are associated with HER2/-neu positivity according to former studies
  • higher values of Ki-67-labeling index were associated with adverse prognostic factors
  • Ki-67-labeling index was associated with larger tumors, higher tumor grade, peritumoral vascular invasion, and HER-2 positivity
  • Nathan Goodyear on 06 Sep 18
     
     Increased disease free survival and overall survival in people with breast cancer with ki-67 <15%
Nathan Goodyear

Dutasteride affects progesterone metabolizing enzyme activity/expression in human breas... - 0 views

www.sciencedirect.com/...S0960076006001397

hormones progesterone cancer breast cancer 5alpha-pregnane 4-pregnenes progesterone metabolites 5 alpha reductase 5 alpha reductase inhibitors

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    Cell culture study finds that 5alpha-reductase inhibition decreased 5alpha-pregnanes and thus inhibited cell proliferation and detachment; this is in contrast to the 4 pregnenes that occur through the enzymes 3alpha-hydroxysteroid oxidoreductase and the 20alpha-hydroxysteroid oxidoreductase, which show anti cell proliferation and cell detachment.
Nathan Goodyear

Interaction between a peroxisome proliferator-activated receptor γ gene polym... - 0 views

hmg.oxfordjournals.org/...2923.long

peroxisome proliferator activated receptor gamma PPAR PPAR-gamma epigenetics obesity fat dietary diet intake gene genetics

shared by Nathan Goodyear on 21 Jan 13 - No Cached
  • uniform dietary recommendations may not be appropriate for all individuals
  • Nathan Goodyear on 21 Jan 13
     
    Peroxisome proliferator-activated receptor gamma plays an important role in obesity and fat generation.  In this study, they showed how the genetic expression of different PPAR gamma genotypes results in altered physiologic response to fat intake in humans.  The interaction between genetics and the environment.
Nathan Goodyear

Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to... - 0 views

clincancerres.aacrjournals.org/...5844.full

prostate cancer DHT metabolite metabolites men male hormone hormones 3-alpha-diol 3-alpha androstanediol

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Nathan Goodyear on 03 Feb 14
     
    Article discusses the the conversion of 3-alpha-diol back to DHT and this role in prostate cancer in androgen deprivation therapy.  What we now know is that this metabolite interacts with ER alpha receptor to promote proliferation.  Carcinogenesis appears to be primarily an estrogen driven process and her in prostate cancer, the androgen metabolites are promoting proliferation through estrogen receptors.
Nathan Goodyear

An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and... - 0 views

www.pnas.org/...13589.full

3-beta androstanediol DHT metabolite prostate cancer ER-beta ER beta CYP7b1 cytochrome male hormone hormones men

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • Although the prostate is an androgen-dependent tissue, estrogens influence both normal functions and pathological changes in this gland
  • This dual action may be due to the existence of two estrogen receptors, ERα and ERβ
  • ERα and ERβ have similar affinities for estradiol-17β
  • ...6 more annotations...
  • In this study we have shown that regulation of the levels of 3βAdiol by CYP7B1 is a key factor in regulation of prostatic growth
  • We provide evidence that proliferating cells in the prostate epithelium have elevated levels of AR and that AR protein but not mRNA levels are regulated by ERβ and its ligand 3βAdiol in the prostate epithelium.
  • because inhibition of 5α-reductase causes accumulation of testosterone and removal of ERβ action increases the level of AR in the prostate, the overall effect of Finasteride would be to favor proliferation of the prostate epithelium
  • studies show that ERβ tends to be lost in advanced prostate cancer.
  • DHEA is converted in the body to 5-androstene-3β,17β-diol, which is also a ligand for estrogen receptors (25, 39) and a substrate for CYP7B1
  • At the peak of proliferation, the proliferating epithelial cells in the ventral prostate expressed high levels of CYP7B1 but had no detectable ERβ, whereas in nonproliferating cells the level of ERβ was high and that of CYP7B1 was low.
  • Nathan Goodyear on 27 Jan 14
     
    3-beta androstanediola, a product of 3alpha-HSD from DHT binds to ER beta and down regulates AR in prostate cancer.  This study proposes that the mechanism is via CYP7B1.  CYP7B1 inactivates 3-beta androstanediol.  Interesting, because 3-beta androstanediol is considered "inactive" when compared to 3-alpha androstanediol and its interaction with ER alpha.  
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views

www.ncbi.nlm.nih.gov/...PMC154104

progesterone metabolites breast cancer 5alpha-reductase 5-alpha pregnene 5-alpha pregnenes 4-pregnene 4-pregnenes

shared by Nathan Goodyear on 30 Jan 14 - No Cached
  • Exposure of human breast cell lines (MCF-7, MCF-10A, and ZR-75-1) to 5α-pregnanes results in changes associated with neoplasia, including increased proliferation and decreased attachment [1], depolymerization of F-actin [2] and decreases in adhesion plaque-associated vinculin
  • Exposure to 4-pregnenes results, in general, in opposite (anti-cancer-like) effects
  • 5αR1 has been detected in various androgen-independent organs, such as the liver and brain
  • ...10 more annotations...
  • 5αR2 has been found predominantly in androgen-dependent organs, such as epididymis and prostate
  • The 5α-pregnanes:4-pregnenes ratio was about 8-fold higher in tumorous than in nontumorous breast tissue after an 8-hour incubation with [14C]progesterone
  • Studies with breast cell lines, showing that 5α-pregnanes stimulate proliferation and decrease attachment of cells
  • both tissue and breast cell line studies suggest that an elevated level of progesterone 5α-reductase activity may be an indicator of breast tumorigenesis, regardless of presence or absence of ER and/or PR
  • 5αR1 is the main isoform expressed in human breast carcinomas [29] and that 5αR2 may not be associated with risk of breast cancer
  • the differences in 5α-pregnane production between the cells is due primarily to a difference in 5αR1 expression
  • As in the case of 5α-reductase activity, the presence or absence of ER and PR do not appear to be related to 5α-reductase expression.
  • the conversion of progesterone to the cancer promoting 5α-pregnanes is significantly higher in the human tumorigenic breast cell lines
  • lthough both 5αR1 and 5αR2 are expressed by these cells, the elevated 5α-reductase activity appears to be the result of significantly greater expression of 5αR1
  • Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for promoting breast cancer progression due to increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes
  • Nathan Goodyear on 30 Jan 14
     
    balance of enzyme production between 5alpha-reductase and 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductase play role in carcinogenesis and proliferation in the balance of production of progesterone metabolites. The 5alpha pregnenes are pro carcinogenic  and the 4-pregnenes are anti carcinogenic.
Nathan Goodyear

Anticancer mechanisms of cannabinoids - 0 views

www.ncbi.nlm.nih.gov/...PMC4791144

THC cannabinoids cancer

shared by Nathan Goodyear on 18 Sep 18 - No Cached
  • modulating key cell signalling pathways involved in the control of cancer cell proliferation and survival
  • cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals
  • Cannabis sativa L. (marijuana)
  • ...41 more annotations...
  • of the approximately 108 cannabinoids produced by C. sativa, Δ9-tetrahydrocannabinol (thc) is the most relevant because of its high potency and abundance in plant preparations
  • Tetrahydrocannabinol exerts a wide variety of biologic effects by mimicking endogenous substances—the endocannabinoids anandamide3 and 2-arachidonoylglycerol4,5—that engage specific cell-surface cannabinoid receptors
  • the cb2 receptor was initially described to be present in the immune system6, but was more recently shown to also be expressed in cells from other origins
  • transient receptor potential cation channel subfamily V, member 1
  • orphan G protein–coupled receptor 55
  • Most of the effects produced by cannabinoids in the nervous system and in non-neural tissues rely on cb1 receptor activation
  • two major cannabinoid-specific receptors—cb1 and cb2
  • cardiovascular tone, energy metabolism, immunity, and reproduction
  • cannabinoids are well known to exert palliative effects in cancer patients
  • best-established use is the inhibition of chemotherapy-induced nausea and vomiting
  • thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer
  • cannabinoid receptors and their endogenous ligands are both generally upregulated in tumour tissue compared with non-tumour tissue
  • cb2 promotes her2 (human epidermal growth factor receptor 2) pro-oncogenic signalling in breast cancer
  • pharmacologic activation of cannabinoid receptors decreases tumour growth
  • endocannabinoid signalling can also have a tumour-suppressive role
  • pharmacologic stimulation of cb receptors is, in most cases, antitumourigenic. Nonetheless, a few reports have proposed a tumour-promoting effect of cannabinoids
  • most prevalent effect is the induction of cancer cell death by apoptosis and the inhibition of cancer cell proliferation
  • impair tumour angiogenesis and block invasion and metastasis
  • thc and other cannabinoids induce the apoptotic death of glioma cells by cb1- and cb2-dependent stimulation
  • Autophagy is primarily a cytoprotective mechanism, although its activation can also lead to cell death
  • autophagy is important for cannabinoid antineoplastic activity
  • autophagy is upstream of apoptosis in the mechanism of cannabinoid-induced cell death
  • the effect of cannabinoids in hormone- dependent tumours might rely, at least in part, on the ability to interfere with the activation of growth factor receptors
  • glioma cells), pharmacologic blockade of either cb1 or cb2 prevents cannabinoid-induced cell death with similar efficacy
  • other types of cancer cells (pancreatic48, breast24, or hepatic43 carcinoma cells, for example), antagonists of cb2 but not of cb1 inhibit cannabinoid antitumour actions
  • thc promotes cancer cell death in a cb1- or cb2-dependent manner (or both) at lower concentrations
  • cannabidiol (cbd), a phytocannabinoid with a low affinity for cannabinoid receptors15, and other marijuana-derived cannabinoids57 have also been proposed to promote the apoptotic death of cancer cells acting independently of the cb1 and cb2 receptors
  • In cancer cells, cannabinoids block the activation of the vascular endothelial growth factor (vegf) pathway, an inducer of angiogenesi
  • In vascular endothelial cells, cannabinoid receptor activation inhibits proliferation and migration, and induces apoptosis
  • cb1 or cb2 receptor agonists (or both) reduce the formation of distant tumour masses in animal models of both induced and spontaneous metastasis, and inhibit adhesion, migration, and invasiveness of glioma64, breast65,66, lung67,68, and cervical68 cancer cells in culture
  • the ceramide/p8–regulated pathway plays a general role in the antitumour activity of cannabinoids targeting cb1 and cb2
  • cbd, by acting independently of the cb1 and cb2 receptors, produces a remarkable anti-tumour effect—including reduction of invasiveness and metastasis
  • cannabinoids can also enhance immune system–mediated tumour surveillance in some contexts
  • ability of thc to reduce inflammation75,76, an effect that might prevent certain types of cancer
  • recent observations suggest that the combined administration of cannabinoids with other anticancer drugs acts synergistically to reduce tumour growth
  • combined administration of gemcitabine (the benchmark agent for the treatment of pancreatic cancer) and various cannabinoid agonists synergistically reduced the viability of pancreatic cancer cells
  • Other reports indicated that anandamide and HU-210 might also enhance the anticancer activity of paclitaxel89 and 5-fluorouracil90 respectively
  • Combined administration of thc and cbd enhances the anticancer activity of thc and reduces the dose of thc needed to induce its tumour growth-inhibiting activity
  • Preclinical animal models have yielded data indicating that systemic (oral or intraperitoneal) administration of cannabinoids effectively decreases tumour growth
  • Combinations of cannabinoids with classical chemotherapeutic drugs such as the alkylating agent temozolomide (the benchmark agent for the management of glioblastoma80,84) have been shown to produce a strong anticancer action in animal models
  • pharmacologic inhibition of egfr, erk83, or akt enhances the cell-death-promoting action of thc in glioma cultures (unpublished observations by the authors), which suggests that targeting egfr and the akt and erk pathways could enhance the antitumour effect of cannabinoids
  • Nathan Goodyear on 18 Sep 18
     
    Good review of the anticancer effects of cananbinoids.
Nathan Goodyear

The role of progesterone metabolites in breast cancer: Potential for new diagnostics an... - 0 views

www.sciencedirect.com/...S0960076004004224

progesterone progesterone metabolites cancer breast cancer hormones

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    changes in progesterone metabolism associated with breast cancer i.e. 5alpha-pregnanes are associated with proliferation in breast cancer and the 4-pregnenes inhibit proliferation and cellular detachment.
Nathan Goodyear

Immunotherapy of C3H/HeJ mammary adenocarcinoma with interleukin-2, mistletoe lectin or... - 0 views

www.sciencedirect.com/...S0959804901001563

immunotherapy IL-2 mistletoe cancer

shared by Nathan Goodyear on 01 Jun 19 - No Cached
  • Nathan Goodyear on 01 Jun 19
     
    Study finds IL-2 reduces cancer proliferation and metastasis; however, mistletoe alone found to stimulate proliferation, though at very low doses i.e. 1 ng/kg, in mouse model.
Nathan Goodyear

Hormetic dose response to L-ascorbic acid as an anti-cancer drug in colorectal cancer c... - 0 views

www.nature.com/...s41598-018-29386-7

hermetic dose response prooxidative low dose vitamin C vitamin sodium dependent vitamin C transporter High dose IV vitamin C SVCT C high dose vitamin C

shared by Nathan Goodyear on 11 Aug 22 - No Cached
  • Nathan Goodyear on 11 Aug 22
     
    Low dose vitamin C, via SVCT, increases tumor proliferation; whereas high dose decreases tumor proliferation.
Nathan Goodyear

The telomerase activator TA-65 elongates short telomeres and increases health span of a... - 0 views

www.ncbi.nlm.nih.gov/...PMC3627294

TA-65 telomere Telomerase telomerase activator aging natural wellness health

shared by Nathan Goodyear on 16 May 16 - No Cached
  • studies have demonstrated that the shortest telomeres are causal of reduced cell viability
  • a stable and enforced expression of telomerase leads to an improved health-span, accompanied by an extension of lifespan
  • TA-65 influences the percentage of cellular short telomeres through the activation of telomerase
  • ...17 more annotations...
  • TA-65 administration during 4 months significantly improved the capacity to uptake glucose after a glucose pulse
  • liver protective action of TA-65
  • A disadvantage of mTERT potentiation could be associated to its capacity to favor proliferation of cancerous cells in murine models
  • TA-65 treated mice presented a similar incidence of malignant cancers at time of death, with a tendency to show decreased sarcomas and slightly increased lymphomas
  • We demonstrate here that TA-65 leads to a significant rescue of short telomeres through telomerase activation
  • TA-65 treatment increases proliferation and mobilization potential of mouse keratinocytes in vitro, a situation mimicking telomerase overexpression
  • TAT2, a similar molecule, have beneficial effects in the activation of CD8+ T lymphocytes from HIV-infected patients where they observe an increase of the proliferative potential and enhancement of cytokine/chemokine production
  • TA-65 resulted in a similar rescue of short telomeres in leukocytes post-treatment as observed with humans, most likely through an activation of telomerase
  • we observe that TA-65 lead to 10 fold increase of telomerase RNA levels in the liver of treated mice comparing to the non-treated same-age cohorts
  • TA-65 regulates telomerase at the transcription level, probably through the regulation of the MAPK pathway
  • TA-65 dependent telomerase activation results in a better organ fitness as demonstrated by the improved scores at the glucose tolerance test and insulin levels at fasting
  • TA-65 supplemented mice also present modest enhancement of the subcutaneous and epidermal thickness, as well as higher bone density, representative of an overall fitness status improvemen
  • TA-65 treated mice present higher levels of RBC and hemoglobin comparing to the control cohorts
  • improved health-span of TA-65 treated mice is not accompanied by increased cancer incidence, which may be related to the fact that TERT levels are very modestly increased in all tissues tested except for the liver
  • systemic telomerase overexpression from the germline leads to protection from aging associated pathologies
  • similar situation could be mimicked expressing telomerase late in life in a telomerase deficient background
  • we observed a higher proliferation rate and a partial protection from cell death in some tissues of TA65 treated mice
  • Nathan Goodyear on 16 May 16
     
    TA-65 shown to increase telomerase activity, and thus telomere length of short telomeres, in mouse study.  
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