Department of Biochemistry and Molecular Biology, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA; Department of Cancer Biology, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
Department of Molecular Medicine, University of Texas Health San Antonio (UTHSA), San Antonio, TX, 78229, USA.
Mol Cell Endocrinol. 2020 Jul 1;511:110859. doi: 10.1016/j.mce.2020.110859. Epub 2020 May 11.
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.
孕激素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。尽管这两种激素所具有的生物学过程有重叠，但人们对两种激素同时表达如何影响其各自的作用知之甚少。孕激素和催乳素通过激活基因表达对乳腺发挥许多作用，要么直接（孕激素与孕激素受体 [PR] 结合），要么间接（催乳素下游激活多种转录因子，最显著的是 STAT5）。我们使用 T47D 乳腺癌细胞中的 RNA-seq 技术，描述了孕激素和催乳素单独或联合作用时调节的基因表达程序。我们发现，两种激素独立和联合执行的转录程序之间存在显著的串扰和微调。我们将转录程序分为四大类。所有由孕激素调节的串扰/微调都依赖于 PR 的表达。此外，PR 被招募到所有受调控基因的增强子区域。有趣的是，尽管 STAT5 在正常和哺乳期乳腺中转导催乳素信号具有典型作用，但在这种乳腺癌细胞系模型系统中，孕激素精细调节的催乳素调控转录程序中，实际上很少依赖 STAT5。总而言之，这些数据表明，在乳腺癌中，孕激素和催乳素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，并且可能通过与在正常乳腺中观察到的不同的转录调节剂。当两种激素都存在时研究基因调控是最具临床意义的，特别是在乳腺癌的背景下。
