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Implications for postpartum reprograming of SEMA7A and SOX9 in mammary cells and breast cancer

ABSTRACT: Postpartum mammary gland involution is a coordinated process of cell death and remodeling that returns the tissue to a near pre-pregnant state following lactation and weaning. In models of postpartum breast cancer, defined as breast cancer diagnosed in women under age 45 and within 10 years of recent childbirth, involution induces durable phenotypes in breast tumor cells that promote progression and are associated with increased risk for therapeutic resistance, metastasis, and death in patients. SRY-Box Transcription Factor 9 (SOX9), a known regulator of mammary stem and progenitor cells, also promotes resistance to therapy and metastasis in breast cancers. Yet the contribution of SOX9 to the involution process is not well understood. We utilized single-cell RNA sequencing of mouse mammary glands during involution to delineate Sox9-expressing cell populations during lactation and involution. We found that Sox9 mRNA is primarily expressed in luminal progenitor cells that are largely absent during lactation and present during early involution. We also reveal that Sox9 is involved in a shift in cell state from lactational to non-lactational and is expressed in the surviving cells during involution. Prior work revealed that Semaphorin-7a (SEMA7A) also promotes cancer stem cell and pro-survival phenotypes in luminal progenitor cells during involution, and we observe a population of luminal progenitor cells that co-expresses Sox9 and Sema7a during involution. Mechanistically, we demonstrate that knockdown of Sox9 in cultured mammary epithelial cells results in increased SEMA7A expression, mesenchymal phenotypes, and loss of lactogenic differentiation capacity, identifying a potential regulatory axis where SOX9 balances SEMA7A expression in normal mammary epithelium and that disruption of this balance results in a dedifferentiated state that resembles mesenchymal cells. We validated a spatial relationship between SOX9 and SEMA7A proteins in a unique set of breast tissue samples from healthy human donors to show co-expression during early involution. In breast cancer datasets, we observe elevated expression of SOX9 and SEMA7A in triple-negative breast cancers, as well as in the mesenchymal subtype of triple-negative breast cancers, suggesting disruption of this regulatory axis in breast cancer. Finally, we observe that co-expression increases metastatic risk in both estrogen receptor-negative and -positive breast cancers. Collectively, these findings define a novel SOX9–SEMA7A relationship in healthy mammary tissues and illustrate how studies of normal progenitor cell phenotypes can delineate cellular mechanisms that contribute to breast tumor progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE319717 | GEO | 2026/05/20

REPOSITORIES: GEO

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Project description:The mammary gland is a dynamic tissue that undergoes most of its development postnatally to accommodate milk production during lactation and then, after weaning, undergoes postpartum involution, a coordinated process of epithelial cell death, remodeling, and inflammation that returns the tissue to a near pre-pregnant state. Yet, the mechanisms employed by some mammary cells to survive for subsequent lactation are not fully understood. Multiple studies suggest that involution is a driver of postpartum breast cancers (PPBCs), or those diagnosed within ten years of childbirth, that exhibit disproportionately high metastatic risk. Prior work implicates SEMA7A in mammary epithelial cell survival during involution and in metastasis of PPBC. We utilized single-cell RNA sequencing of mouse mammary glands during lactation and involution to delineate Sema7a-expressing populations during tissue development and remodeling. We found that Sema7a is expressed in a small subset of epithelial cells but is more predominantly expressed in endothelial and pericyte populations, whereas the developmentally regulated transcription factor Sox9 is highly expressed in epithelial subsets. We further show that SOX9 and SEMA7A expression changes across lactation and involution in mouse and in a unique set of human breast tissues collected from healthy donors during lactation and post-weaning. Using in vitro models of lactogenic differentiation and involution, we demonstrate a relationship between SOX9 and SEMA7A whereby knockdown of Sox9 in mammary epithelial cells increases SEMA7A expression and induces epithelial/mesenchymal hybrid phenotypes, identifying a potential regulatory axis in which SOX9 restrains SEMA7A-driven epithelial plasticity. Since SEMA7A is a driver of PPBC recurrence, we analyzed breast cancer datasets for SEMA7A and SOX9 to reveal that co-expression of SOX9 and SEMA7A correlates with metastatic risk in TNBC. Together, these findings define a previously unrecognized SOX9–SEMA7A relationship in the postpartum mammary gland and illustrate how studies of normal development can identify cellular mechanisms that may be susceptible to transformation and contribute to PPBC progression. This project aims to characterize transcriptomic changes in mouse mammary gland tissue across the reproductive stages of lactation and involution in wild-type mice. The goal is to understand cell-type-specific gene expression changes, with a focus on immune and epithelial compartments, and explore the potential role of SOX9 and SEMA7A in these processes.

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Implications for postpartum reprograming of SEMA7A and SOX9 in mammary cells and breast cancer

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