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Nathan Goodyear

Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors i... - 0 views

advances.sciencemag.org/...e1501924.full

progesterone PR progesterone receptors progesterone receptor cancer breast cancer hormones

shared by Nathan Goodyear on 29 Jun 16 - No Cached
  • The presence and activity of PR significantly affect the prognostic value of ER.
  • The observed loss of PR protein expression in a subset of ER+/PR+ breast cancers, because of hypermethylation or deletion of the PR gene locus, results in the loss of ER prognostic value
  • These findings emphasize the clinical value of assessing both PR and ER expression in breast cancer samples
  • ...7 more annotations...
  • PR is an essential modulator of ER-regulated genes but also that it significantly contributes to the prognostic value of ER in ER+/PR+ breast cancers
  • PR-regulated genes have independent prognostic value, and the presence of PR correlates with favorable clinicopathological outcomes
  • this study demonstrates that progestin-activated PR redirects ER chromatin binding and functions as a genomic estrogen agonist and as a phenotypic estrogen antagonist in ER+/PR+ breast cancer cells and human tumors
  • Approximately 80% of ER+ breast cancers are also positive for PR,
  • In isolation, both hormones activate or inhibit cellular processes in similar directions, although the magnitude of these effects is less for progestin alone than for estrogen alone
  • PR-mediated antagonism of estrogenic phenotypes is well documented
  • joint activation of ER and PR antagonized ER-regulated oncogenic processes
  • Nathan Goodyear on 29 Jun 16
     
    WOW!!  study finds that progesterone through PR activity antagonizes ER protein expression by the cell.  This has huge implications in breast cancer and possible prostate cancer.  But then again, women don't need progesterone; only estrogen.  The presence of PR correlates with improved clinicopathological outcomes.  The authors do seem to get confused about progesterone and progestins.  They are not one in the same.
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
  • ...31 more annotations...
  • 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

Circulating 2-hydroxy and 16-α hydroxy estrone levels and risk of breast canc... - 1 views

www.ncbi.nlm.nih.gov/...PMC2562592

estrogen metabolism menopause post-menopause post menopause estrogen metabolite 2-OH-estrone 16-alpha-OH-estrone 2:16alpha-OH estrone breast cancer risk hormone hormones

shared by Nathan Goodyear on 21 Aug 14 - No Cached
  • 2-OH estrogens bind to the estrogen receptor (ER) with affinity equivalent to or greater than estradiol
  • previous prospective studies have not observed any significant associations with either 2-OH or 16α-OH estrone or the ratio of the two metabolites and breast cancer risk overall.
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      whether that risk is increased or decreased
  • it has been hypothesized that metabolism favoring the 2-OH over the 16α-OH pathway may be inversely associated with breast cancer risk (28).
  • ...24 more annotations...
  • they may act as only weak mitogens (14, 15), or as inhibitors of proliferation
  • While 16α-OH estrone binds to the ER with lower affinity than estradiol, it binds covalently (18-20) and once bound, fails to down-regulate the receptor (21). Thus, 16α-OH estrone stimulates cell proliferation in a manner comparable to estradiol in ER+ breast cancer cell lines
  • No significant associations have been observed between 2-OH estrone and breast cancer risk
  • In this large prospective study of 2-OH and 16α-OH estrone metabolites and breast cancer risk, we did not observe any significant associations overall with either individual metabolite or with the ratio of the two metabolites
  • our results do not support the hypothesis that metabolism favoring the 2-OH estrone pathway is more beneficial to breast cancer risk than that favoring the 16α-OH estrone pathway
  • To date, several epidemiologic studies have examined the association between the 2-OH and 16α-OH estrogen metabolites and breast cancer risk with inconclusive results.
  • circulating estrogen levels have been associated more strongly with ER+/PR+ tumors than with ER-/PR- tumors
  • we observed positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with lower BMI and women with ER-/PR-tumors,
  • we observed significant positive associations of both 2-OH estrone and the 2:16α-OH estrone ratio with ER-/PR-tumors
  • Three (30, 32, 33) of four (30-33) studies observed RRs above 1 for the association between 16α-OH estrone and breast cancer risk (range of RRs=1.23-2.47); none of the point estimates was statistically significant though one trend was suggestive
  • we observed a suggestive inverse association with 16α-OH estrone and a significant positive association with the 2:16α-OH estrone ratio among lean women, suggesting possible associations in a low estrogen environment.
  • No significant associations have been observed between 2-OH estrone, 16α-OH estrone, or the 2:16α-OH estrone ratio and breast cancer risk and the direction of the estimates is not consistent across studies.
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      better worded is no consistent, significant associations.   There are some studies that point to the 16 catecholestrogen and increased cancer risk; limited studies show negative effects of 2 catecholestrogens on cancer risk and prospective studies available pretty much dispel the idea that the 2:16 ratio has an risk predictability.
  • based on animal studies, 2-OH estrone and the 2:16α-OH estrone ratio have been hypothesized to be inversely associated with breast cancer risk
  • 16α-OH estrone increases unscheduled DNA synthesis in mouse mammary cells (27) and hence also may be genotoxic
  • Although 2-OH estrogens are capable of redox cycling, the semiquinones and quinones (i.e., the oxidized forms) form stable DNA adducts that are reversible without DNA destruction
  • In our population of PMH nonusers, we observed no associations with ER+/PR+ tumors, but significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with ER-/PR- tumors
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      one of the few studies to find this association between 2 catecholestrogens and the 2:16 ratio and ER-/PR-tumors
  • Animal and in vitro studies have shown that hydroxy estrogens can induce DNA damage either directly, through the formation of quinones and DNA adducts, or indirectly, through redox cycling and the generation of reactive oxygen species
    • Nathan Goodyear
      Nathan Goodyear on 08 Oct 15
       
      genotoxic via directe DNA adducts and indirectly via ROS; this is in addition to the proliferative effect
  • we observed a significant positive association between the 2:16α-OH estrone ratio and breast cancer risk among lean women
  • No significant associations have been observed with the 2:16α-OH estrone ratio
  • In the Danish study, no associations were observed with either ER+ or ER- tumors among PMH nonusers
  • significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio were observed among PMH users with ER+, but not ER-, tumors
  • it is possible that the genotoxicity of 2-OH estrone plays a role in hormone receptor negative tumors
  • 4-OH estrogens have a greater estrogenic potential than 2-OH estrogens, given the lower dissociation rate from estrogen receptors compared with estradiol (61), and are potentially more genotoxic since the quinones form unstable adducts, leading to depurination and mutation in vitro and in vivo
  • the balance between the catechol (i.e., 2-OH and 4-OH) and methoxy (i.e., 2-Me and 4-Me) estrogens may impact risk
  • Nathan Goodyear on 21 Aug 14
     
    The risks of estrogen metabolism are not clear cut.  Likely never will be due to the complexity of individual metabolism.  This study found no correlation between 2OH-Estrone and 2OH:16alpha-Estrone and breast cancer risk in ER+/PR+ breast cancer.  Translated: no benefit in breast cancer risk in 2OH-Estrone metabolism or increased 2OH:16alpha estrone metabolism.  There was a positive association between 2OH-Estrone and 2:16alpha-Estrone in women with ER-/PR- tumors and low BMI.
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Nathan Goodyear

ScienceDirect.com - The Journal of Steroid Biochemistry and Molecular Biology - Differe... - 0 views

www.sciencedirect.com/...S0960076097001192

progesterone receptor progesterone receptors PR-A PR-B progesterone receptor receptors hormone hormones

shared by Nathan Goodyear on 11 May 13 - No Cached
  • Nathan Goodyear on 11 May 13
     
    progesterone receptor status varies through a woman's menstrual cycle. PR-A dominates throughout, but the PR-A to PR-B ratio declines up to ovulation.
Nathan Goodyear

Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. - 0 views

genesdev.cshlp.org/...2266.full.pdf+html

progesterone inflammation PR receptors PR-A PR-B

shared by Nathan Goodyear on 09 Nov 12 - No Cached
  • Nathan Goodyear on 09 Nov 12
     
    study shows that mice lacking PR-A and PR-B (progesterone receptors) have increased uterine inflammation.   Again, the inflammatory/pro-inflammatory effects of hormones may be regulated through receptors.  This may be the reason that different stages of life elicit a different response with the same hormone.
Nathan Goodyear

Immunohistochemical Expression of Estrogen and Progesterone Receptors in Human Colorect... - 0 views

www.ncbi.nlm.nih.gov/...PMC3215447

estrogen progesterone ER estrogen receptor estrogen receptors ER alpha ER beta ER-alpha ER-beta PR progesterone receptor progesterone receptors

shared by Nathan Goodyear on 09 Jun 14 - No Cached
  • Nathan Goodyear on 09 Jun 14
     
    Study finds ER and PR increase along the timeline of tumor initiation.  The authors point to likely association that ER and PR expression is associated with and key to initiating colorectal transformation.  A lot to be determined from this study.  IF this were entirely true, then what to explain the 35% lower colorectal cancer risk in women vs men?  Likely ER and PR pertubance plays a significant role is likely, but the mere expression--yet to be determined.
Nathan Goodyear

http://www.turkjcancer.org/pdf/pdf_TJC_489.pdf - 0 views

www.turkjcancer.org/...pdf_TJC_489.pdf

colon colorectal cancer ER PR estrogen receptor estrogen receptors progesterone receptor progesterone receptors

shared by Nathan Goodyear on 09 Jun 14 - No Cached
  • Nathan Goodyear on 09 Jun 14
     
    The relationship between ER and PR and colorectal cancer is yet to be determined.  It is not outside the realm of possibility that a standardization of ER/PR in colorectal cancer is unlikely.  Each cancer is unique.  There are probably some generalizations that can be made, but complete generalizations of ER/PR in colorectal cancer in women is unlikely.
Nathan Goodyear

Progesterone Receptor Inhibits Aromatase and Inflammatory Response Pathways in Breast C... - 0 views

mend.endojournals.org/...1812.long

progesterone receptor receptors PR breast cancer anti-inflammatory

shared by Nathan Goodyear on 12 Nov 12 - No Cached
  • Nathan Goodyear on 12 Nov 12
     
    Progesterone receptor (PR) shown to provide an important anti-inflammatory role in breast cancer in this study.  PR shown to increase NF-kappaB inhibitor IkBalpha, shown to inhibit aromatase activity, shown to inhibit COX-2 expression and shown to inhibit HER-2/neu expression.
Nathan Goodyear

Breast Cancer Patients with Progesterone Receptor PR-A-Rich Tumors Have Poorer Disease-... - 0 views

clincancerres.aacrjournals.org/...2751.full

progesterone receptor progesterone receptors A B PR-A PR-B breast cancer ER+ PR+ hormone hormones progesterone receptor receptors survival

shared by Nathan Goodyear on 26 Nov 12 - No Cached
  • Nathan Goodyear on 26 Nov 12
     
    Balance of progesterone receptor A and B shown to influence survival rates in ER+/PR+ breast cancer on hormonal therapy.
Nathan Goodyear

Mapping and Characterization of the Functional Domains Responsible for the Differential... - 0 views

www.jbc.org/...32889.long

progesterone receptor progesterone receptors PR-A PR-B progesterone receptor receptors

shared by Nathan Goodyear on 27 Nov 12 - No Cached
  • Nathan Goodyear on 27 Nov 12
     
    different functions of PR-A and PR-B.
Nathan Goodyear

Estrogen receptor (ER) β, a modulator of ERα in the uterus - 0 views

www.pnas.org/...5936.full

receptors ER-alpha ER-beta hormones hormone

shared by Nathan Goodyear on 16 Aug 12 - No Cached
  • induction of PR is an ERα-mediated event and repression of epithelial PR is ERβ mediated.
  • Nathan Goodyear on 16 Aug 12
     
    ER alpha and ER beta have different effects on the uterus in this mice model.  ER beta modulates ER alpha.  ER beta decreases PR, whereas ER alpha increases PR.
Nathan Goodyear

An N-terminally truncated third p... [J Steroid Biochem Mol Biol. 1997] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...9408082

progesterone receptor progesterone receptors PR-C C progesterone receptor receptors

shared by Nathan Goodyear on 26 Nov 12 - No Cached
  • Nathan Goodyear on 26 Nov 12
     
    progesterone receptor C is a shortened form of PR-A and PR-B.
Nathan Goodyear

Oestrogen and progesterone receptor expression in melasma: an immunohistochemical analy... - 0 views

www.ncbi.nlm.nih.gov/...20337826

melasma hormones progesterone estrogen ER beta ER PR estrogen receptor progesterone receptor

shared by Nathan Goodyear on 18 Oct 16 - No Cached
  • Nathan Goodyear on 18 Oct 16
     
    Both ER and PR increase in melasma: ER-beta in epidermal and dermis lesions versus PR only in epidermal lesions.
Nathan Goodyear

5'-Heterogeneity in human progesterone recept... [Mol Endocrinol. 1990] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...2082185

progesterone receptors PR PR-A PR-B PR-C human

shared by Nathan Goodyear on 09 Nov 12 - No Cached
  • Nathan Goodyear on 09 Nov 12
     
    article describes 3 progesterone receptors: A, B, and C.
Nathan Goodyear

Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform ... - 0 views

www.nursa.org/retrieveFile.cfm

progesterone receptor progesterone receptors A B PR-A PR-B progesterone receptor receptors

shared by Nathan Goodyear on 12 Nov 12 - No Cached
  • Nathan Goodyear on 12 Nov 12
     
    Good discussion of PR receptors. This article focus' on the different receptors, mainly A and B, and the nuclear transcriptional signaling.
Nathan Goodyear

Colocalization of progesterone receptors A and B by dual immunofluourescent histochemis... - 0 views

jcem.endojournals.org/...2963.full.pdf

progesterone receptor progesterone receptors PR-A PR-B progesterone receptor receptors

shared by Nathan Goodyear on 24 Nov 12 - No Cached
  • Nathan Goodyear on 24 Nov 12
     
    PR-A and PR-B and regulation of the human menstural cycle.
Nathan Goodyear

Progesterone Receptor-A and -B Have Opposite Effects on Proinflammatory Gene Expression... - 0 views

jcem.endojournals.org/...E719.abstract

progesterone progesterone receptors PR A PR B pregnancy anti-inflammatory labor

shared by Nathan Goodyear on 25 May 12 - No Cached
  • Nathan Goodyear on 25 May 12
     
    Progesterone is known to have anti-inflammatory action.  This study looked at the anti-inflammatory action of progesterone on the myometrium of the uterus during pregnancy.  The anti-inflammatory effect, in this study, was through Progesterone Receptor B.  There was a change in the dominance to PR A late in pregnancy.  This would promote inflammatory signaling and thus contractions with the onset of labor.
Nathan Goodyear

Membrane 5alpha-pregnane-3,20-dio... [J Steroid Biochem Mol Biol. 2005] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...16154741

progesterone metabolite metabolites 3-alpha pregnene 3-alpha pregnenes 5-alpha pregnene 5-alpha pregnenes estradiol hormone hormones breast cancer

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites are present on the membrane of ER/PR + as well as ER/PR - breast cancer cell lines.  The balance of 5 alpha pregnane:3 alpha pregnane regulates tumor genesis.  Estradiol increased 5 alpha pregnane receptors as well as 5 alpha pregnane unregulated itself via autocrine activity.  The 3 alpha pregnenes, 3 alpha hydroxyprogesterone and 20 alpha-dihydroprogesterone, decrease the 5 alpha pregnane receptors via paracrine activity.
Nathan Goodyear

Plasma membrane receptors for the... [Biochem Biophys Res Commun. 2000] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...10860824

hormone receptors hormones progesterone metabolite metabolites 3-alpha pregnene 5-alpha pregnene 5-alpha pregnenes

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    The receptors for 5 alpha progesterone and 3 alpha hydroxyprogesterone are distinct from other hormone receptors.  These receptors are plasma membrane bound.  Through these receptors, these progesterone metabolites initiate autocrine and paracrine activity.  E2 increased 5 alpha progesterone receptors.  This is very important in ER-/PR- breast cancer, but does still have significance in ER+/PR+ cancer as well.
Nathan Goodyear

Progesterone Metabolites Regulate Breast Cell Tumors - 0 views

www.medscape.com/...809131

progesterone metabolites progesterone metabolites 5alpha-dihydroprogesterone 3alpha-dihydroprogesterone hormones hormone breast cancer

shared by Nathan Goodyear on 18 Jun 14 - No Cached
  • Nathan Goodyear on 18 Jun 14
     
    As much fanfare that is given to ER/PR + breast cancer, the large percentage of breast cancers are ER/PR -.  Thus, hormonal therapy doesn't work...at least that is how the story goes. This study finds the metabolites of Progesterone to be equally telling.  Two Progesterone metabolites play significant roles in growth versus inhibition of growth.  The metabolite 5alpha-dihydroprogesterone is procarcingenic in in vitro and in vivo studies and the metabolite 3alpha-dihydroprogesterone inhibits the pro growth effects in the same in vitro and in vivo studies.
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