Abstract Postpartum breast cancers (PPBCs), defined as breast cancers diagnosed within ten years of childbirth, carry a significantly higher risk of metastasis and mortality compared to breast cancers diagnosed in nulliparous women. Preclinical studies implicate postpartum mammary gland involution, a period marked by extensive epithelial cell death, tissue remodeling, and inflammation, as a driver of this poor prognosis. However, the epithelial programs that govern cell survival, plasticity, and transformation susceptibility during the postpartum window remain incompletely understood. We have previously published that SEMA7A, which is linked to PPBC progression, is involved in the survival of luminal progenitor cells (LPCs) during postpartum involution. Thus, we utilized single-cell RNA sequencing to further define SEMA7A-expressing cells in mouse mammary glands during both lactation and involution to show that SEMA7A is primarily expressed on cells of the endothelium, including pericytes, but less so on mammary epithelial cells. We also revealed that Sox9, a transcription factor that is known to be expressed on mammary epithelial cells, is expressed on LPCs in the mammary gland during involution. Notably, LPCs have been suggested as key cells-of-origin for several mammary tumors. We describe the expression pattern of SOX9 throughout lactation and involution, showing that SOX9 expression changes over the course of involution in both mouse and human samples. Functional in vitro models of lactogenic differentiation and involution with immortalized mammary epithelial cells were utilized to define the relationship between SOX9 and SEMA7A in these epithelial states. We found that SEMA7A is low in these epithelial cells across the differentiation and involution process and that SOX9 knockdown in mammary epithelial cells results in increased SEMA7A expression and drives mesenchymal cell phenotypes, uncovering a regulatory axis in which SOX9 restrains SEMA7A-mediated cellular plasticity. Analysis of breast cancer datasets shows that dysregulation of this axis, resulting in co-expression of SOX9 and SEMA7A, correlates with metastatic risk. Together, these findings reveal a previously unrecognized SOX9-SEMA7A signaling axis in the postpartum mammary gland and highlight how studies of normal development can uncover mechanisms of PPBC progression and point toward new avenues for prevention. Citation Format: Lauren M. Cozzens, Brendan Hinckley, Sonali Jindal, Virginia F. Borges, Pepper Schedin, Traci Renae Lyons. SOX9 and SEMA7A regulate epithelial cell plasticity in the postpartum mammary gland with implications for postpartum breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 850.
Cozzens et al. (Fri,) studied this question.