Androgen-like and anti-androgen-like effects of antiprogestins in human mammary cancer cells

Hackenberg, R.; Hannig, Kurt; Beck, Simone; Schmidt-Rhode, P.; Scholz, Arne; Schulz, K.-D.

doi:10.1016/0959-8049(95)00616-8

Cited by 14 publications

(4 citation statements)

References 18 publications

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“…Furthermore, whereas the ability of progesterone to impair male sexual behavior could be related to its antiandrogenic and antiestrogenic properties (Hendricks, 1992), this is not the case with RU486, which apparently does not bind to estrogen receptors (Philibert, 1984). Although at high doses RU486 has sometimes been reported to be weakly antiandrogenic (e.g., Hackenberg et al, 1996;Terouanne et al, 2000), it is more often reported to be a moderate androgen receptor agonist (e.g., Kemppainen, Lane, Sar, & Wilson, 1992;Lu et al, 1991;Miyamoto, Yeh, Wilding, & Chang, 1998), a property that is unlikely to contribute to the present results. Lastly, in a few cases, RU486 has been suggested to act as a progestin agonist in non-neuronal tissue (e.g., Bowden, Hissom, & Moore, 1989), but this may be true only under very specific cellular conditions (Beck, Weigel, Moyer, Nordeen, & Edwards, 1993;Sartorius, Tung, Takimoto, & Horwitz, 1993).…”

Section: Effects Of Neonatal Ru486 On Reproduction In Ratsmentioning

confidence: 56%

Effects of neonatal RU486 on adult sexual, parental, and fearful behaviors in rats.

Lonstein¹,

Quadros²,

Wagner³

2001

Behavioral Neuroscience

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Exposure to gonadal hormones during perinatal life influences later behavior. The finding that sex differences exist in progestin receptor expression in the perinatal rat brain suggests differential sensitivity of male and female brains to progesterone (C. K. Wagner, A. N. Nakayama, & G. J. De Vries, 1998). Because these sex differences are in neural sites that influence sexually differentiated sexual, parental, and fearful behaviors in adults, this study examined the effects of administering the progestin receptor antagonist RU486 for the first 10 days after birth on these behaviors in adulthood. Neonatal RU486 significantly reduced sexual behavior in males but did not impair reproduction in females. Neonatal RU486 did not affect parental responses of virgin rats exposed to pups (sensitization) but reduced fear in the elevated plus-maze in both sexes. Treatment of pups with RU486 affected neither mother-litter interactions nor plasma testosterone levels in males during or after treatment. These results suggest that neonatal exposure to progesterone, in addition to androgens and estrogens, influences behavioral development in rats.

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Section: Effects Of Neonatal Ru486 On Reproduction In Ratsmentioning

confidence: 56%

Effects of neonatal RU486 on adult sexual, parental, and fearful behaviors in rats.

Lonstein¹,

Quadros²,

Wagner³

2001

Behavioral Neuroscience

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“…4e). Importantly ZK98299 does not alter ER or PR levels [51] and has decreased antiglucocorticoid activity and lacks antiandrogen activity often ascribed to earlier antiprogestins [52]. ZK98299 therefore allows us to conclude that the tumor-cell protective effects we observe are due to the presence of unliganded PR.…”

Section: Discussionmentioning

confidence: 93%

Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint

Badtke¹,

Jambal²,

Dye³

et al. 2011

Breast Cancer Res Treat

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Whether the presence of steroid receptors in luminal breast cancers renders them resistant to taxanes remains uncertain. Here we assess the role of progesterone receptors (PR) on taxane-induced cell death. We previously showed that estrogen receptor (ER)-positive human breast cancer cells that inducibly express PR-A or PR-B isoforms were protected from taxane-stimulated apoptosis when compared to the identical cells lacking PR. Surprisingly, PR-dependent protection occurred in the absence of progesterone, demonstrating that the unliganded receptors were biologically active. The present studies demonstrate that unliganded PR, focused on PR-A, protect breast cancer cells from taxane-stimulated apoptosis. The studies identify genes regulated by taxanes in isogenic ER-positive cells that either lack or express PR-A. We show that unliganded PR-A alters the gene expression pattern controlled by taxanes, especially multiple genes involved in the spindle assembly checkpoint, a group of proteins that insure proper attachment of microtubules to kinetochores during mitosis. Importantly, taxanes and unliganded PR regulate many of these genes in opposite directions. As a result, mitotic slippage is exacerbated by the presence of PR, leading to an increase in the number of multinucleated cells both in vitro and in xenograft tumors. We describe a simple new assay for assessing multinucleation in paraffin sections. We speculate that rather than inducing cell death, unliganded PR exploits multinucleation to promote cell survival from taxane therapy. This can be prevented with antiprogestin.

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“…Given RU486 is well-characterized for its partial agonism, it is possible that ESR1 mutant cells uniquely express a particular strong PR coactivator that confers the partial agonism of RU486 in this context. Another possibility is that RU486 alternatively stimulates other nuclear receptors such as glucocorticoid 93 , 100 or potentially even androgen receptor 101 to reprogram BCKs expression. The reversed PR pharmacological response in ESR1 mutant cells is intriguing and warrants future investigation.…”

Section: Discussionmentioning

confidence: 99%

ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

McGinn

et al. 2022

Nat Commun

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Estrogen receptor alpha (ER/ESR1) is frequently mutated in endocrine resistant ER-positive (ER+) breast cancer and linked to ligand-independent growth and metastasis. Despite the distinct clinical features of ESR1 mutations, their role in intrinsic subtype switching remains largely unknown. Here we find that ESR1 mutant cells and clinical samples show a significant enrichment of basal subtype markers, and six basal cytokeratins (BCKs) are the most enriched genes. Induction of BCKs is independent of ER binding and instead associated with chromatin reprogramming centered around a progesterone receptor-orchestrated insulated neighborhood. BCK-high ER+ primary breast tumors exhibit a number of enriched immune pathways, shared with ESR1 mutant tumors. S100A8 and S100A9 are among the most induced immune mediators and involve in tumor-stroma paracrine crosstalk inferred by single-cell RNA-seq from metastatic tumors. Collectively, these observations demonstrate that ESR1 mutant tumors gain basal features associated with increased immune activation, encouraging additional studies of immune therapeutic vulnerabilities.

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Androgen-like and anti-androgen-like effects of antiprogestins in human mammary cancer cells

Cited by 14 publications

References 18 publications

Effects of neonatal RU486 on adult sexual, parental, and fearful behaviors in rats.

Effects of neonatal RU486 on adult sexual, parental, and fearful behaviors in rats.

Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint

ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation

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