Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Medical Scientist Training Program (MSTP), University of California, San Francisco, San Francisco, CA 94518, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Syst. 2022 Aug 17;13(8):644-664.e8. doi: 10.1016/j.cels.2022.06.005. Epub 2022 Jul 20.
The rise and fall of estrogen and progesterone across menstrual cycles and during pregnancy regulates breast development and modifies cancer risk. How these hormones impact each cell type in the breast remains poorly understood because they act indirectly through paracrine networks. Using single-cell analysis of premenopausal breast tissue, we reveal a network of coordinated transcriptional programs representing the tissue-level response to changing hormone levels. Our computational approach, DECIPHER-seq, leverages person-to-person variability in breast composition and cell state to uncover programs that co-vary across individuals. We use differences in cell-type proportions to infer a subset of programs that arise from direct cell-cell interactions regulated by hormones. Further, we demonstrate that prior pregnancy and obesity modify hormone responsiveness through distinct mechanisms: obesity reduces the proportion of hormone-responsive cells, whereas pregnancy dampens the direct response of these cells to hormones. Together, these results provide a comprehensive map of the cycling human breast.
雌激素和孕激素在月经周期和怀孕期间的升降调节着乳房的发育，并改变着癌症的风险。这些激素如何影响乳房中的每一种细胞类型仍知之甚少，因为它们通过旁分泌网络间接作用。通过对绝经前乳腺组织的单细胞分析，我们揭示了一个协调转录程序的网络，代表了组织水平对激素水平变化的反应。我们的计算方法 DECIPHER-seq 利用了乳腺组成和细胞状态在人与人之间的可变性，以揭示个体间共同变化的程序。我们利用细胞类型比例的差异来推断出一组程序，这些程序来自受激素调节的直接细胞-细胞相互作用。此外，我们证明了先前的妊娠和肥胖通过不同的机制改变了激素的反应性：肥胖降低了对激素有反应的细胞的比例，而妊娠则抑制了这些细胞对激素的直接反应。总之，这些结果为周期性人类乳房提供了一个全面的图谱。
