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Nathan Goodyear

The 4-Pregnene and 5α-Pregnane Progesterone Metabolites Formed in Nontumorous... - 0 views

cancerres.aacrjournals.org/...936.full

progesterone metabolism cancer risk 4-pregnene 5alpha-pregnane

shared by Nathan Goodyear on 17 Feb 12 - No Cached
  • We report here the first evidence that tumorous breast tissue exhibits elevated 5α-reductase activity, which promotes significant increases in 5α-pregnanes, especially 5αP,4 whereas the normal (nontumorous) breast tissue produces more 4-pregnenes, especially 3αHP
  • 3αHP and other 4-pregnenes inhibit, whereas 5αP and other 5α-pregnanes stimulate, breast cell proliferation and detachment
  • it is evident that breast tissue can convert progesterone into two classes of metabolites: the δ-4-pregnenes (which retain the C4–5 double bond), and the 5α-reduced 21-carbon steroids (5α-pregnanes)
  • ...12 more annotations...
  • irreversible action of 5α-reductase
  • in normal (nontumorous) breast tissue, the 4-pregnene metabolites of progesterone greatly exceeded the 5α-pregnanes, whereas in tumorous tissue, 5α-pregnanes exceeded 4-pregnenes.
  • These differences in 5α-pregnane and 4-pregnene amounts were largely attributable to differences in 5αP and 3αHP production in tumorous and nontumorous tissues
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
  • These findings suggest greatly elevated 5α-reductase activity in tumorous, as compared with nontumorous, breast tissue.
  • progesterone metabolites that retain the C-4 double bond (i.e., the 4-pregnenes) exert an antiproliferative effect in the three cell lines that were tested, whereas the 5α-pregnanes stimulate breast cell line proliferation.
  • the degree of mitogenicity would be determined by the ratio of 5α-pregnanes:4-pregnenes. Tissues with a high 4-pregnene:5α-pregnane ratio would maintain a higher degree of normalcy, whereas those with a high 5α-pregnane:4-pregnene ratio would tend toward tumorigenicity
  • The observations that progesterone metabolites affect both ER-positive and ER-negative cells as well as tumorigenic (MCF-7) and nontumorigenic (MCF-10A) cells strengthen the argument that these factors may be endocrinologically relevant for all forms of breast cancer.
  • progesterone metabolites as the active endocrine/paracrine/autocrine factors
  • Estrogen-based therapies elicit responses in only one-third of all breast cancer patients, and most of these show relapse.
  • the metabolic activities were in general similar, regardless of the age and ER state of the patient or whether she was pre- or postmenopausal.
    • Nathan Goodyear
      Nathan Goodyear on 27 Jan 14
       
      Interesting that the effect of progesterone metabolites were found to be independent from ER status, age, and pre/post menopause
  • Nathan Goodyear on 17 Feb 12
     
    Different progesterone metabolites shown to have different tumor effects.  Implications are that, just as estrogen metabolism effects cancer risk, so does progesterone metabolism.
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

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

Expression of progesterone metabolizing enzyme genes (AKR1C1, AKR1C2, AKR1C3, SRD5A1, S... - 0 views

bmccancer.biomedcentral.com/...1471-2407-4-27

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

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    Breast cell culture study finds increase 5alpha-reductase 1/2 activity and decreased 3alpha HSO.  This fits previous previous studies that show that increased 5alpha pregnanes is associated with increased proliferation and increased detachment; in contrast to decreased 4-pregnene metabolites.
Nathan Goodyear

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

bmccancer.biomedcentral.com/...1471-2407-3-9

hormones progesterone progesterone metabolites cancer breast cancer 5alpha reductase 5alpha-pregnane 4-pregnene

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    cell culture study finds that increased 5alpha reductase activity and resultant 5alpha-pregnanes are associated with breast cancer cell lines.  This is in contrast to the 4-pregnenes.  In fact, decreased 4-pregnenes are found in the same breast cancer cell lines; this suggests decreased 20alpha-HSO and 3alpha-HSO activity.
Nathan Goodyear

Plasma Membrane Receptors for the Cancer-Regulating Progesterone Metabolites,... - 0 views

www.sciencedirect.com/...S0006291X0092847X

Hormones progesterone metabolites receptors progesterone cancer breast cancer 5alpha-pregnane estradiol

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    The receptor for the progesterone 5alpha pregnane, 5alpha-P, is unregulated in breast cancer cell line MCF-7.  Estradiol increases the receptor expression.  Not only is there an enzymatic effect in these progesterone pathways, but the receptor is equally unregulated.
Nathan Goodyear

Progesterone metabolites in breast cancer - 0 views

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

progesterone metabolism metabolites breast cancer hormones progesterone metabolites

shared by Nathan Goodyear on 12 Jun 14 - No Cached
  • In breast tumor tissue and tumorigenic cell lines, 5α-reductase activity and mRNA expression are significantly higher, whereas 3α- and 20α-HSO activities and mRNA expression are significantly lower than in normal breast tissue and nontumorigenic cells
  • Studies using various breast cell lines have shown that 5αP and 3αHP have opposing actions in terms of cell proliferation and adhesion; 5αP stimulates cell proliferation (through increased mitosis and decreased apoptosis) and cell detachment, whereas 3αHP suppresses cell proliferation (through decreased mitosis and increased apoptosis) and detachment
  • the paracrine/ autocrine functions of 5αP are cancer-promoting and those of 3αHP are cancer-inhibiting
  • Nathan Goodyear on 12 Jun 14
     
    Awesome article on progesterone metabolism in breast cancer.  The author, weibe, describes 2 categories of progesterone metabolites in breast tissue: 5alpha-pregnanes and 4-pregnenes.  The author describes 3 primary enzymes that control the balance between these 2 metabolites--5alpha reductase, 3alpha-HSO, and 20alpha-HSO.  The resultant balance of 5alpha-dihydroprogesterone and 3alpha-dihydroprogesterone helps to determine the cancer potential of breast tissue.
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

BMC Cancer | Full text | Activity and expression of progesterone metabolizing... - 0 views

www.biomedcentral.com/...9

breast cancer progesterone metabolites progesterone metabolites hormone hormones

shared by Nathan Goodyear on 18 Jun 14 - No Cached
  • Nathan Goodyear on 18 Jun 14
     
    Might the enzymes be more important than the hormones themselves?  The number is important i.e. progesterone, but how the number came to be is more important as it points to the underlying etiology.  Here, the balance of enzymes are found to direct cell line tumor potential.  The enzyme 5alpha-reductase increased production of the 5alpha-pregnanes which increased tumor potential.  In contrast, the enzymes 20alpha-hydrosteroid oxidoreductase and 3alpha-hydroxysteroid oxidoreductase increase production of the 4alpha-pregnanes, which decreased tumor potential.
Nathan Goodyear

The endogenous progesterone metabolite, 5α-pregnane-3,20-dione, decreases cel... - 0 views

link.springer.com/...ENDO:16:1:07

hormones progesterone progesterone metabolites 5alpha-pregnane breast cancer cancer

shared by Nathan Goodyear on 07 Oct 16 - No Cached
  • Nathan Goodyear on 07 Oct 16
     
    The progesterone metabolite, 5alpha-pregnanes, likely involved in the genesis of breast cancer through increased proliferation and decreased cell adhesion.
Nathan Goodyear

Breast Cancer Research | Full text | Progesterone metabolites regulate induction, growt... - 0 views

breast-cancer-research.com/...R38

breast cancer progesterone metabolite metabolites 5-alpha-pregnanediol 4-pregnene

shared by Nathan Goodyear on 23 Jan 14 - No Cached
  • Nathan Goodyear on 23 Jan 14
     
    5alpha pregnanes and 4 pregnanes stimulate ER and PR negative breast cancer cells.  Progesterone metabolites stimulate or inhibit cancer potential independent of receptor status.  Though we know that progesterone metabolite balance can increase receptor binding.
Nathan Goodyear

Membrane 5α-pregnane-3,20-dione (5αP) receptors in MCF-7 and MCF-10A breast c... - 0 views

www.sciencedirect.com/...S0960076005003420

breast cancer progesterone metabolites progesterone metabolites hormone hormones

shared by Nathan Goodyear on 18 Jun 14 - No Cached
  • Nathan Goodyear on 18 Jun 14
     
    Very interesting study.  In ER/PR + breast cancer cells, Estradiol and 5alpha-dihydroprogestorone increase the membrane expression of 5alpha-dihydroprogesterone receptors.  This has a pro-growth, pro-metastatic potential.  In contrast, the metabolites 3alpha-dihdroprogesterone and 20alpha-HP inhibit the same membrane receptor expression thus giving an antigrowth, anti-metastatic potential.
Nathan Goodyear

The 4-Pregnene and 5α-Pregnane Progesterone Metabolites Formed in Nontumorous... - 0 views

cancerres.aacrjournals.org/...936.long

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

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    Good discussion of the different effects of progesterone metabolites in breast cancer cell lines (in vitro).  This article focused on the biochemical balance of 5alpha pregnane: 3alpha HP.  The increase in this ration promoted proliferation and metastasis, where a decreased ratio did the opposite
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

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

Progesterone-induced stimulation of mammary tumorigenesis is due to the proge... - 0 views

www.sciencedirect.com/...S0960076015000060

5 alpha reductase inhibitors 5 alpha reductase progesterone 5alpha-pregnane breast cancer

shared by Nathan Goodyear on 07 Jul 20 - No Cached
  • Nathan Goodyear on 07 Jul 20
     
    5 alpha reductase inhibitor, finasteride inhibits pro-tumor progesterone metabolite pathway.
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