Regulation of estrogen receptor (ER) levels in MCF-7 cells by progesterone metabolites

Pawlak, Kevin J.; Wiebe, John P.

doi:10.1016/j.jsbmb.2007.05.030

Cited by 30 publications

(12 citation statements)

References 36 publications

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“…In this regard, 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 [43]. Furthermore, because both tumorigenic and normal (nontumorigenic) breast cells respond to the opposing actions of 5αP and 3αHP, the relative concentrations of the progesterone metabolites in the microenvironment may also play a role in maintaining normalcy of breast tissues in general, regardless of ER/PR status.…”

Section: Discussionmentioning

confidence: 99%

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

et al. 2013

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IntroductionOf the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous 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. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.MethodsER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.ResultsOnset 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. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.ConclusionsThe studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. 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. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

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Section: Discussionmentioning

confidence: 99%

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

et al. 2013

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“…The receptors exhibit only negligible affinity for other steroids such as estradiol-17␤, progesterone and its other metabolites, androgens and corticosteroids [6]. In addition to various opposing actions with respect to adhesion and proliferation, 5␣P and 3␣HP also have opposing effects on the regulation of 5␣PR [8] and ER [9] numbers.…”

Section: Introductionmentioning

confidence: 99%

Opposing actions of the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines

Wiebe

Beausoleil

Zhang

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…The significant increase in plasma progesterone concentrations in the RU486-treated rats on GD 17 may be responsible for the increase in myometrial Esr2 [22,23]. An alternative explanation for the different effects of RU486 treatment on RXFP1 could be the higher circulating levels of relaxin on GD 17 compared with GD 8.…”

Section: Regulation Of Myometrial Rxfp1mentioning

confidence: 97%

Progesterone Withdrawal, and Not Increased Circulating Relaxin, Mediates the Decrease in Myometrial Relaxin Receptor (RXFP1) Expression in Late Gestation in Rats1

Vodstrcil¹,

Shynlova²,

Westcott³

et al. 2010

Biology of Reproduction

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In pregnant rats, a significant decrease in myometrial relaxin family peptide receptor 1 (RXFP1) expression, indicative of a functional relaxin withdrawal for activation of myometrial contractions, occurs in late gestation and during spontaneous labor. This coincides with the highest level of circulating relaxin and a decrease in progesterone. We investigated the potential regulatory role of these two systemic factors on myometrial RXFP1 expression by examining the effects of the antiprogestin RU486 and a monoclonal antibody against rat relaxin (MCA1) in pregnant rats. Rats were injected with RU486 on Gestational Day (GD) 7, 16, or 19 and were killed on GD 8, 17, or 20. RU486 caused a significant reduction in myometrial RXFP1. Plasma progesterone and 17beta-estradiol levels were increased in RU486-treated animals compared with controls. RU486 treatment also caused significant increases in myometrial Esr1 and Vegf and a decrease in Esr2. MCA1 was administered i.v. to rats from GD 17 to GD 19. On GD 20, no significant effect of MCA1 treatment on myometrial RXFP1 expression was observed compared with controls. Furthermore, there was no change in Esr1 or Esr2. A significant reduction in myometrial Vegf, however, was observed. We suggest that blocking progesterone action with RU486 increases plasma 17beta-estradiol and myometrial Esr1 and results in decreased RXFP1 expression. In summary, myometrial RXFP1 expression is mediated mainly by progesterone and not circulating relaxin in pregnant rats.

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Regulation of estrogen receptor (ER) levels in MCF-7 cells by progesterone metabolites

Cited by 30 publications

References 36 publications

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and progesterone receptor-negative human breast cell tumors

Opposing actions of the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP) on mitosis, apoptosis, and expression of Bcl-2, Bax and p21 in human breast cell lines

Progesterone Withdrawal, and Not Increased Circulating Relaxin, Mediates the Decrease in Myometrial Relaxin Receptor (RXFP1) Expression in Late Gestation in Rats1

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