TY - JOUR T1 - Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks JF - bioRxiv DO - 10.1101/430611 SP - 430611 AU - Lyndsay M Murrow AU - Robert J Weber AU - Joseph Caruso AU - Christopher S McGinnis AU - Kiet Phong AU - Philippe Gascard AU - Alexander D Borowsky AU - Tejal A Desai AU - Matthew Thomson AU - Thea Tlsty AU - Zev J Gartner Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/21/430611.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -