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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.
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

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

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
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