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.

中文翻译：

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乳腺癌细胞中孕酮和催乳素调节基因表达的相互微调。

孕酮和催乳素是参与乳腺发育和重塑的两种关键激素。因此，这两种激素都与乳腺癌有关。尽管归因于这两种激素的生物学过程之间存在重叠，但对于两种激素的共表达如何影响它们的个体作用知之甚少。孕酮和催乳素通过激活基因表达对乳腺发挥许多作用，直接（孕酮，与孕酮受体 [PR] 结合）或间接（催乳素下游激活多个转录因子，最显着的是 STAT5）。在 T47D 乳腺癌细胞中使用 RNA-seq，我们表征了由孕激素和催乳素单独或组合调节的基因表达程序。我们发现每种激素独立和组合执行的转录程序之间存在显着的串扰和微调。我们将转录程序分为四大类。所有显示受孕酮调节的串扰/微调都取决于 PR 的表达。此外，PR 被招募到所有调节基因的增强子区域。有趣的是，尽管 STAT5 在正常和泌乳乳腺中转导催乳素信号传导方面具有典型作用，但在这种乳腺癌细胞系模型系统中，几乎没有由孕酮微调的催乳素调节转录程序实际上依赖于 STAT5。累积起来，这些数据表明，孕酮和催乳素在乳腺癌中的相互作用以比以前认为的更复杂和微妙的方式影响基因表达，并且可能通过与正常乳腺中观察到的转录调节因子不同的转录调节因子。当两种激素都存在时研究基因调控在临床上最相关，特别是在乳腺癌的背景下。