Summary
Reproductive history and body weight are two important breast cancer risk factors. Prior pregnancy (parity) reduces lifetime risk by up to 50%, and obesity reduces premenopausal risk by up to 45%. Here, we use single-cell RNA sequencing to directly link these risk factors with tumor-protective changes in epithelial cell proportions and hormone signaling in the premenopausal breast. We show that parity reduces the proportion of transformation-susceptible luminal cells and increases the proportion of tumor-suppressive myoepithelial cells in the epithelium. Additionally, we identify two distinct mechanisms by which parity and obesity contribute to reduced hormone signaling. First, parity reduces the per-cell transcriptional response to ovarian hormones in hormone-responsive cells. Second, parity and obesity reduce the overall proportion of hormone-responsive cells. Both mechanisms lead to a decreased paracrine signaling response in myoepithelial cells. Together these findings provide mechanistic insight into how BMI and parity affect the mammary epithelial microenvironment to modify breast cancer susceptibility.
Footnotes
This version of the manuscript represents our updated findings based on sequencing 19 additional samples, for a total of 28 samples. All figures and text have been substantially revised.
