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Breast cancer cells can recognize and respond to different levels of progestins to achieve different phenotypic outputs [ATAC-seq]

ABSTRACT: The steroid hormone progesterone, acting through its nuclear progesterone receptor (PR), has complex physiologic activities with different levels of hormones manifesting distinct and sometimes opposing phenotypic responses in target tissues. However, most of what is currently known about the transcriptional activity of PR comes from studies performed using progestins at levels that are in the high physiologic range (>10nM), relevant only in the luteal phase of the reproductive cycle and pregnancy in humans. These studies do not consider the non-linearity of responses to progestins that exist in physiology and are not informative as to the mechanisms by which low levels of progestins, as occurs during menopause (0.1-0.3nM), exert their biological activities. Thus, we undertook to define the mechanisms which enable cells to recognize and respond to different levels of progestins.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249939 | GEO | 2025/12/01

REPOSITORIES: GEO

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Breast cancer cells can recognize and respond to different levels of progestins to achieve different phenotypic outputs [RNA-seq]

Project description:The steroid hormone progesterone, acting through its nuclear progesterone receptor (PR), has complex physiologic activities with different levels of hormones manifesting distinct and sometimes opposing phenotypic responses in target tissues. However, most of what is currently known about the transcriptional activity of PR comes from studies performed using progestins at levels that are in the high physiologic range (>10nM), relevant only in the luteal phase of the reproductive cycle and pregnancy in humans. These studies do not consider the non-linearity of responses to progestins that exist in physiology and are not informative as to the mechanisms by which low levels of progestins, as occurs during menopause (0.1-0.3nM), exert their biological activities. Thus, we undertook to define the mechanisms which enable cells to recognize and respond to different levels of progestins.

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Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [mouse]

Project description:Hormonal contraception exposes women to different synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect cell proliferation in the normal breast epithelium and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins strongly induce the PR target and mediator of PR signaling induced cell proliferation Receptor Activator of NF-κB Ligand (Rankl), previously implicated in breast carcinogenesis, whereas other progestins fail to do so. We developed xenografts of normal human breast epithelial cells (HBECSs) to the milk ducts of immunocompromised female mice and show that they remain hormone-responsive. Using HBECSs from 36 women, we show that testosterone-related progestins, desogestrel, gestodene, and levonorgestrel, induce PSA (KLK3) and promote their proliferation, whereas the anti-androgenic progestins, which have shown anti-androgenic properties in reporter assays, chlormadinone acetate and cyproterone acetate, do not. Pharmacological inhibition of the androgen receptor (AR) inhibits PR agonist and levonorgestrel-induced RANKL expression and both pharmacological and genetic AR inhibition reduce levonorgestrel-driven breast epithelial cell proliferation in vivo. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Thus, different progestins have distinct biological activities in the breast epithelium that should be taken into account for more informed choices in hormonal contraception.

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Xenografted breast epithelia reveal differences in growth stimulation among contraceptive progestins related to androgenic properties [human]

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Breast cancer cells can recognize and respond to different levels of progestins to achieve different phenotypic outputs

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Physiological Vascular Permeability Requires Induction of Endothelial NR4A1 by Progesterone Receptor [RNA-Seq]

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Physiological Vascular Permeability Requires Induction of Endothelial NR4A1 by Progesterone Receptor [RNA-Seq]

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