Reciprocal fine-tuning of progesterone and prolactin-regulated gene expression in breast cancer cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE150477 | GEO | 2020/05/14
REPOSITORIES: GEO
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Project description:Reciprocal fine-tuning of progesterone and prolactin-regulated gene expression in breast cancer cells
| PRJNA632540 | ENA
Project description:Progesterone and prolactin are two key hormones involved in development and remodeling of the mammary gland. As such, both hormones have been linked to breast cancer. Despite the overlap between biological processes ascribed to these two hormones, little is known about how co-expression of both hormones affects their individual actions. Progesterone and prolactin exert many of their effects on the mammary gland through activation of gene expression, either directly (progesterone, binding to the progesterone receptor [PR]) or indirectly (multiple transcription factors being activated downstream of prolactin, most notably STAT5). Using RNA-seq in T47D breast cancer cells, we characterized the gene expression programs regulated by progestin and prolactin, either alone or in combination. We found significant crosstalk and fine-tuning between the transcriptional programs executed by each hormone independently and in combination. We divided and characterized the transcriptional programs into four broad categories. All crosstalk/fine-tuning shown to be modulated by progesterone was dependent upon the expression of PR. Moreover, PR was recruited to enhancer regions of all regulated genes. Interestingly, despite the canonical role for STAT5 in transducing prolactin-signaling in the normal and lactating mammary gland, very few of the prolactin-regulated transcriptional programs fine-tuned by progesterone in this breast cancer cell line model system were in fact dependent upon STAT5. Cumulatively, these data suggest that the interplay of progesterone and prolactin in breast cancer impacts gene expression in a more complex and nuanced manner than previously thought, and likely through different transcriptional regulators than those observed in the normal mammary gland. Studying gene regulation when both hormones are present is most clinically relevant, particularly in the context of breast cancer.
| S-EPMC8941988 | biostudies-literature
Project description:The hormone prolactin is implicated in the pathogenesis of breast cancer, and a subset of prolactin-induced gene expression is mediated by HDAC6 activity. The NSAID, bufexamac, is a fairly specific inhibitor of HDAC6 and HDAC10. We used bufexamac in combination with prolactin treatment in MCF7 cells to determine differential expression under these conditions.
2016-05-07 | GSE81217 | GEO
Project description:The hormone prolactin is implicated in the pathogenesis of breast cancer, and a subset of prolactin-induced gene expression is mediated by CypA activity. The non-immunosuppressive prolyl isomerase inhibitor, NIM811, is an inhibitor of CypA. We used NIM811 in combination with prolactin treatment in T47D cells to determine differential expression under these conditions.
2020-06-03 | GSE151635 | GEO
Project description:Effects of estradiol, progesterone, prolactin and oxytocin on miRNA levels in T47D human breast cells
| PRJNA1102023 | ENA
Project description:The hormone, prolactin, has been implicated in breast cancer pathogenesis and regulates chromatin engagement by the transcription factor, STAT5A. STAT5A is known to inducibly bind promoters and cis-regulatory elements genome wide, though the mechanisms by which it exerts specificity and regulation of target gene expression remain enigmatic. We previously identified HDAC6 and HMGN2 as cofactors that facilitate prolactin induced, STAT5A mediated gene expression. Here, multi-condition STAT5A, HDAC6, and HMGN2 ChIP-seq with parallel condition RNA-seq are utilized to reveal the cis-regulatory landscape and cofactor dynamics underlying prolactin stimulated gene expression in breast cancer. We find that prolactin regulated genes are significantly enriched for cis-regulatory elements bound by HDAC6 and HMGN2, and that inducible STAT5A binding at enhancers, rather than promoters, conveys specificity for prolactin regulated genes. The selective HDAC6 inhibitor, ACY-241, blocks prolactin induced STAT5A chromatin engagement at cis-regulatory elements as well as a significant proportion of prolactin stimulated gene expression. We identify functional pathways known to contribute to the development and/or progression of breast cancer that are activated by prolactin and inhibited by ACY-241. Additionally, we find that the DNA sequences underlying shared STAT5A and HDAC6 binding-sites at enhancers are differentially enriched for estrogen response elements (ESR1 and ESR2 motifs) relative to enhancers bound by STAT5A alone. Gene set enrichment analysis identifies significant overlap of ERα regulated genes with genes regulated by prolactin, particularly prolactin regulated genes with promoters or enhancers co-occupied by both STAT5A and HDAC6.
2021-01-26 | GSE165452 | GEO
Project description:Human infants are born to breastfeed. While 50% of lactating persons report struggling to make enough milk, there are no governmentally-approved drugs to enhance lactation1. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant,Prolactin-eXtra Long-acting(Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG1 Fc domain designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. Our Prolactin-XL has a serum half-life of 70.9h in mice, 2,625-fold longer than endogenously active prolactin alone (70.9h v. 0.027h). We demonstrate that Prolactin-XL increases milk production and restores growth of pups fed by dams with pharmacologically-ablated lactation. We show that Prolactin-XL-enhanced lactation is accompanied by reversible, alveolar cell-driven changes in mammary gland morphology. Prolactin-XL treatment was associated with no identifiable pathology or adverse side effect in the lactating mice or nursing pups. This work establishes long-acting prolactins as a potentially powerful pharmacologic means to combat insufficient lactation. Implications for future research in lactating mammary gland biology and a potential preclinical path for developing Prolactin-XL for use in lactating persons are discussed.
2024-07-16 | GSE270276 | GEO
Project description:Most breast cancers are luminal, depending on estrogens for growth. The remainder lack estrogen receptors, are hormone-resistant and basal-like. It is thought that breast cancers arise from self-renewing normal stem cells that have undergone malignant transformation. However currently reported cancer stem cells are hormone insensitive and generate basal, rather than luminal tumors. We now describe true luminal hormone-responsive breast cancer stem cells that express estrogen and progesterone receptors. Their self-renewal capacity is protected by progesterone. Stem cell levels are depleted by estrogens as tumors transition into differentiated and homogeneous luminal states. But, if added to estrogens, progesterone promotes heterogeneity and “rescues” the stem cells. By keeping luminal cancer stem cells “safe”, progesterone, widely used for contraception and hormone replacement, could be harmful to breast cancer survivors or women with occult disease.
2016-01-31 | GSE65407 | GEO
Project description:We examined the global gene expression pattern of T cells regulated by progesterone to gain further insights into the regulatory mechanisms of progesterone. We found 325-347 cord blood T cell genes up or down-regulated by P4 in the presence or absence of exogenous TGFb1. Peripheral blood T cells were relatively unresponsive with only 30-70 genes regulated by P4. IL-6 receptor (IL-6R) expression was greatly down-regulated by progesterone in cord blood, but not PB, T cells. Overall, these differences in gene expression are consistent with the differential responses of cord blood and peripheral blood T cells to progesterone. To gain insights into the differences of progesterone and control dendritic cells, we performed a microarray study and found ~180 genes regulated by progesterone in dendritic cells. The gene expression information suggests that progesterone has the potential to alter dendritic cell responses to cytokines, chemokine production, and migration which in combination would control T cell differentiation.
2012-03-02 | GSE22025 | GEO
Project description:Primary hyperparathyroidism is a common endocrine disorder frequently affecting postmenopausal women. In this study we have investigated expression of the prolactin receptor (PRLr) in a panel of 37 sporadic parathyroid tumours, as well as functionality in vitro in cultured parathyroid tumour cells. High levels of the prolactin receptor gene (PRLR) transcripts were demonstrated in parathyroid tissues as compared to other reference tissues and breast cancer cells. PRLr products of 60/70 kDa were highly expressed in all parathyroid tumours. In addition varying levels of the 80 kDa PRLr isoform, with known proliferative activity, were demonstrated. In parathyroid tumours PRLr immunoreactivity was observed in cytoplasm in all cases and in addition in the plasma membrane (n = 12) or enlarged lysosomes (n = 4). In normal parathyroid rim PRLr was expressed in cytoplasm and granulae. In in vitro studies of short-term cultured human parathyroid tumour cells prolactin stimulation was associated with transcriptional changes in JAK/STAT, RIG-I like receptor and type II interferon signaling pathways as documented by gene expression profiling. Moreover, PRLR gene expression in parathyroid tumors was significantly inversely correlated with plasma total Ca2+ levels. In conclusion, the prolactin receptor was found highly abundant in human parathyroid gland, parathyroid tumours, correlated with patient Ca2+ levels and functionally responsive to physiological levels of prolactin. These findings suggest a role for the prolactin receptor in human parathyroid adenomas. Expression profiling was done in parathyroid adenomas subjected to prolactin treatment in culture. In addition, corresponding paraffin sections were obtained for verification of PRLr expression by immunohistochemistry. 200 mg/L prolactin (recombinant humanM-BM- prolactin, Cat. No. JM-4687-50, MBL Woburn, MA) was added to 1M-CM-^W 10^6 attached parathyroid tumour cells. Cells were harvested using RNAlater (QIAGEN) and homogenized with QIAshredder for RNA extraction after 3 h and 24 h in culture, respectively. Negative controls were collected in parallel with each case at the same time points. RNA was extracted using QIA Cube, and quality assessed with Bioanalyser and Nanodrop. Expression array profiling and data analysis was done at the KI core facility Bioinformatics and Expression Analysis (BEA, Novum, Huddinge) using the Affymetrix platform and the TITAN ST 1.1 array. A total of 16 samples were analysed including 4 parathyroid adenomas cultured for 3 h or 24 h in the presence of prolactin plus control samples cultured in parallel without prolactin.
2012-04-30 | E-GEOD-32387 | biostudies-arrayexpress