Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA390280 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5679860.fastq.gz | Fastqsanger.gz | |||
| SRR5679870.fastq.gz | Fastqsanger.gz | |||
| SRR5679880.fastq.gz | Fastqsanger.gz | |||
| SRR5679890.fastq.gz | Fastqsanger.gz | |||
| SRR5679900.fastq.gz | Fastqsanger.gz |
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Project description:An incomplete understanding of dose-dependent progesterone receptor (PR) biology has led to the suboptimal exploitation of PR as a therapeutic target. While hormone replacement therapies (HRT) containing low-doses of synthetic progestogens (progestins) have been associated with an increased risk of breast cancer, high-dose progestin therapies have beneficial therapeutic effects in some patients with breast cancer. Herein we report that PR subcellular localization, post-trans3lational modifications, stability, chromatin binding, responsive gene expression and downstream biology differ considerably as a function of progestin concentration. Dose-dependent transcriptional profiling revealed that different concentrations of progestin elicit classic sigmoidal and/or biphasic gene induction at distinct target gene sets. Notably, when compared to high doses of progestin, low-dose treatments lead to minimal nuclear translocation of PR while supporting robust induction of a subset of target genes, indicating that PR occupancy has a complex relationship to target gene induction. Interestingly, high but not low-dose progestin treatments lead to increased phosphorylation at Ser294 and is associated with higher receptor turnover. Furthermore, while low-dose treatments stimulate cell proliferation, high-dose treatments do not result in significant cell cycle progression to S phase. Similar biphasic and sigmoidal patterns of gene induction were observed in human breast tumor explants treated with various concentrations of progestin, underscoring the need to fine tune the dosage of PR-targeting therapies. Given the wide range of medical applications of PR target therapy, our discovery of distinct dose-dependent PR biology may have important clinical implications.
2020-06-13 | GSE99986 | GEO
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.
2021-05-12 | GSE155273 | GEO
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.
2021-05-12 | GSE155272 | GEO
Project description:Combined menopausal hormone therapy is associated with increased breast cancer risk in postmenopausal women. In our previous studies, progesterone receptor membrane component 1 (PGRMC1) was shown to play a role in progestins’ mode of action, resulting in enhanced proliferation of breast cancer cells. Here we describe a potential mechanism by which PGRMC1 contributes to breast cancer progression via interaction with prohibitins, inhibiting their function as transcription factor repressors, thereby facilitating estrogen receptor alpha (ERα) transcriptional activity and enhancing oncogenic signaling upon treatment with certain progestins, such as norethisterone and dydrogesterone.
2022-02-16 | PXD028537 | Pride
Project description:Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progestins
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Project description:ChIPseq analysis of patient-derived luminal breast cancer xenografts with progestins
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Project description:Here, we investigate therapy-induced senescence (TIS) as a reversible mechanism of drug resistance in breast cancer cells. High-dose doxorubicin treatment was used to induce TIS in four distinct breast cancer cell lines and the drug resistance/sensitivity pattern of parental and TIS cells were investigated using a panel of FDA-approved anticancer molecules.
Proteome analysis confirmed the presence of the Senescence-Associated Secretory Phenotype (SASP), altered spliceosomal activity and proteins with significant role in immune evasion.
2024-11-19 | PXD058028 | JPOST Repository
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.
2025-12-01 | GSE249943 | GEO
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.
2025-12-01 | GSE249939 | GEO
Project description:RNAseq analysis of patient-derived luminal breast cancer xenografts treated with progestins
| PRJNA359750 | ENA