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Transcriptomic Profile of Breast Tissue of Premenopausal Women Following Treatment with Progesterone Receptor Modulator: Secondary Outcomes of a Randomized Controlled Trial

ABSTRACT: Progesterone receptor antagonism is gaining attention due to progesterone's recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial examining changes in breast mRNA expression following mifepristone treatment in healthy women. We analyzed 32 paired breast biopsies from 16 healthy premenopausal women at baseline and after two months of mifepristone treatment. In total, twenty-seven differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this expression gene signature was associated with breast carcinogenesis and significantly correlated with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transciptome following mifepristone treatment in healthy breast tissue in vivo, enhancing the understanding of progesterone receptor modulator and its potential protective effects against breast cancer by investigating its action in healthy breast tissue.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252145 | GEO | 2024/07/15

REPOSITORIES: GEO

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Effects of the Progesterone Receptor Antagonist Mifepristone on the Molecular Expression on Breast tissue in Premenopausal Healthy Women

Project description:Effects of the Progesterone Receptor Antagonist Mifepristone on the Molecular Expression on Breast tissue in Premenopausal Healthy Women

| PRJNA433842 | ENA

Beneficial effects of mifepristone treatment in breast cancer patients selected by the progesterone receptor isoform ratio: Results from the MIPRA trial

Project description:Background: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas expressing higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of opportunity trial to determine the therapeutic effects of mifepristone in breast cancer patients selected by their high PRA/PRB isoform ratio (MIPRA; NCT02651844). Patients and Methods. Twenty patients bearing luminal breast carcinomas with PRA/PRB>1.5 (determined by Western blots), and PR ≥50%, naive from previous treatment, were included for mifepristone treatment (200 mg/day p.o.; 14 days). Core needle biopsies (CNB) and surgical samples were formalin-fixed for immunohistochemical studies, and others were snap-frozen to perform RNA-Seq, proteomics, and/or Western blots studies. Plasma mifepristone levels were determined by mass spectrometry. The primary endpoint was the comparison of Ki-67 expression pre- and post-treatment. Results: A 49.62% decrease in Ki-67 staining was registered in all surgical specimens compared to baseline (p=0.0003). Using the pre-specified response parameter (30% relative reduction) we identified 14/20 responders. Mifepristone induced gland differentiation, an increase in tumor-infiltrating lymphocytes, a decrease in hormone receptors and pSer118ER expression, and an increase in calregulin, p21, p15, and activated caspase3 expression. RNA-Seq and proteomics studies identified downregulated pathways related to cell proliferation and upregulation of those related to immune bioprocesses and extracellular matrix re-modeling pathways. Conclusion: Our results support the use of mifepristone in luminal breast cancer patients with high PRA/PRB ratios. The combined effects of mifepristone with estrogen receptor modulators deserves clinic evaluation in these patients, to improve endocrine treatment responsiveness.

2022-10-17 | GSE212690 | GEO

Molecular changes in premenopausal estrogen receptor-positive primary breast cancer after oophorectomy

Project description:For premenopausal women with primary ER+ breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore characterized the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER+ breast cancer for two weeks prior to mastectomy. Plasma estradiol concentrations decreased from 421±305 to 24.1±24.5 pmol/l (mean±sd) 24 hours after OvX and to 8.8±7.3pmol/l two weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR<1%) with an absolute mean fold-change (FC) ≥1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes, proliferation-associated genes and putative progesterone-regulated genes were strongly down-regulated. The gene expression changes did not differ according to HER2 status and correlated strongly with those after aromatase inhibitor (AI) treatment in 81 postmenopausal women. However, after OvX the mean FC was significantly higher compared to AI. In conclusion, changes in tumoural gene expression after OvX were largely similar but of a greater magnitude to those observed after AI in postmenopausal patients but OvX appeared to have a greater effect on progesterone-regulated genes than AI.

2018-02-14 | GSE97221 | GEO

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in Uterine Fibroids and Breast Cancer (ChIP-Seq)

Project description:Analysis of genes regulated by RU486 (an progesterone antagonist) in human breast cancer T47D cells and human uterine leiomyoma smooth muscle cells. The hypothesis is that RU486 inhibits tumor growth by inactivating the transcription of multiple genes which trigger critical signaling pathways to induce tumorigenesis in both breast caner and uterine leomyoma. Tissue-specific and common patterns of gene regulation may determine the therapeutic effects of antiprogestins in uterine leiomyoma and breast cancer. We applied ChIP-seq to identify PR-interaction sites in T47D breast cancer cells and primary uterine leiomyoma cells treated with RU486.

2012-09-11 | E-GEOD-40724 | biostudies-arrayexpress

PGRMC1 promotes progestin-dependent proliferation of breast cancer cells by binding prohibitins resulting in activation of ERα signaling

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

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in Uterine Fibroids and Breast Cancer (ChIP-Seq)

2012-09-11 | GSE40724 | GEO

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in Uterine Fibroids and Breast Cancer (Expression BeadChip)

2012-09-11 | GSE40725 | GEO

Antiprogestins reduce epigenetic field cancerization in breast tissue of young healthy women

Project description:Breast cancer is a leading cause of death in premenopausal women. Progesterone drives expansion of luminal progenitor cells, leading to the development of poor-prognostic breast cancers. However, it is not known if antagonising progesterone can prevent breast cancers in humans. We suggest that targeting progesterone signalling could be a means of reducing features which are known to promote breast cancer formation.

2022-05-16 | GSE157126 | GEO

Genomic signature of parity in the breast of premenopausal women

Project description:Full-term pregnancy (FTP) at an early age confers long-term protection against breast cancer, in this study, we evaluated gene expression changes induced by parity in the breast of premenopausal women. Gene expression profiling of normal breast tissue from 30 nulliparous (NP) and 79 parous (P) premenopausal volunteers were performed using Affymetrix microarrays. In addition to a discovery/validation analysis, we conducted analysis of gene expression differences in P vs. NP women as a function of time since last FTP.

2019-03-19 | GSE112825 | GEO

Progesterone-mediated gene expression in the human endometrial stromal compartment during the implantation window

Project description:Progesterone regulated genes in the endometrial stromal compartment were studied in proven fertile women using laser dissection capture microscopy followed by microarray. Endometrial biopsies were obtained from women before (control group, n=9) and after (study group, n=9) treatment with mifepristone. Stromal cells were isolated by Laser-capture microdissection and RNA was extracted. The gene expression was analyzed by microarray and reconfirmed by real-time PCR.

2014-07-16 | E-GEOD-59447 | biostudies-arrayexpress

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