Department of Animal Science, University of California, Davis, Davis, California 95616, USA.
Department of Animal Science, University of Vermont, Burlington, Vermont 05405, USA.
Endocrinology. 2022 Mar 1;163(3). doi: 10.1210/endocr/bqab256.
Successful lactation and the risk for developing breast cancer depend on growth and differentiation of the mammary gland (MG) epithelium that is regulated by ovarian steroids (17β-estradiol [E] and progesterone [P]) and pituitary-derived prolactin (PRL). Given that the MG of pigs share histomorphogenic features present in the normal human breast, we sought to define the transcriptional responses within the MG of pigs following exposure to all combinations of these hormones. Hormone-ablated female pigs were administered combinations of E, medroxyprogesterone 17-acetate (source of P), and either haloperidol (to induce PRL) or 2-bromo-α-ergocryptine. We subsequently monitored phenotypic changes in the MG including mitosis, receptors for E and P (ESR1 and PGR), level of phosphorylated STAT5 (pSTAT5), and the frequency of terminal ductal lobular unit (TDLU) subtypes; these changes were then associated with all transcriptomic changes. Estrogen altered the expression of approximately 20% of all genes that were mostly associated with mitosis, whereas PRL stimulated elements of fatty acid metabolism and an inflammatory response. Several outcomes, including increased pSTAT5, highlighted the ability of E to enhance PRL action. Regression of transcriptomic changes against several MG phenotypes revealed 1669 genes correlated with proliferation, among which 29 were E inducible. Additional gene expression signatures were associated with TDLU formation and the frequency of ESR1 or PGR. These data provide a link between the hormone-regulated genome and phenome of the MG in a species having a complex histoarchitecture like that in the human breast, and highlight an underexplored synergy between the actions of E and PRL during MG development.
成功的哺乳和患乳腺癌的风险取决于乳腺（MG）上皮的生长和分化，其受卵巢类固醇（17β-雌二醇[E]和孕酮[P]）和垂体源性催乳素（PRL）调节。鉴于猪的 MG 具有正常人类乳房中存在的组织形态发生特征，我们试图确定在暴露于这些激素的所有组合后，猪的 MG 中的转录反应。给去势的雌性猪施用 E、醋酸甲地孕酮（P 的来源）以及氟哌啶醇（诱导 PRL）或 2-溴-α-麦角隐亭的组合。随后，我们监测了 MG 的表型变化，包括有丝分裂、E 和 P 的受体（ESR1 和 PGR）、磷酸化 STAT5（pSTAT5）的水平以及终末导管小叶单位（TDLU）亚型的频率；然后将这些变化与所有转录组变化相关联。雌激素改变了大约 20%的所有基因的表达，这些基因主要与有丝分裂有关，而 PRL 刺激了脂肪酸代谢和炎症反应的元素。一些结果，包括 pSTAT5 的增加，突出了 E 增强 PRL 作用的能力。将转录组变化回归到几个 MG 表型中，揭示了与增殖相关的 1669 个基因，其中 29 个是 E 诱导的。与 TDLU 形成和 ESR1 或 PGR 的频率相关的其他基因表达特征。这些数据在具有与人类乳房相似的复杂组织形态学的物种中，将受激素调节的 MG 基因组与表型之间建立了联系，并强调了 E 和 PRL 在 MG 发育过程中的作用之间未被充分探索的协同作用。
