The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks.

中文翻译：

---

上皮比例和转录状态的变化是绝经前乳腺癌的主要危险因素

人的乳房对雌激素和孕酮的反应会经历终生的重塑，但是激素的暴露也会增加患乳腺癌的风险。在这里，我们使用单细胞分析来确定乳房组成和细胞状态影响激素信号传导的不同机制。我们表明，怀孕前会降低激素反应性（HR +）上皮细胞的转录反应，而高体重指数（BMI）会降低总体HR +细胞比例。这些明显的变化都通过有效降低源自HR +细胞的旁分泌信号的幅度来影响相邻细胞。因为已知怀孕和高BMI可以预防绝经前女性的激素依赖性乳腺癌，所以我们的发现直接将乳腺癌的风险与激素反应中人与人之间的异质性联系起来。更广泛地，