# SEMA7A in postpartum mammary gland development and cellular transformation

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $401,885

## Abstract

Background: We seek to further our understanding of normal mammary gland biology and determine
how pregnancy associated changes in the mammary gland may contribute to development of breast
cancers. Though pregnancy is well-known to provide a protective effect against breast cancer risk, all women
who give birth experience a transient increase in breast cancer risk following each pregnancy. The magnitude
and length of this elevated risk is largely determined by the woman's age at first birth and for women over 30 at
the time of first pregnancy the protective effect likely never occurs. Postpartum breast cancers (PPBC), defined
as breast cancers diagnosed within 5-10 years of last childbirth, are more than twice as likely to become
metastatic and result in death. This devastating diagnosis affects ~12,000 women annually. In 2006, for the
first time, the number of women having children in their 30s was greater than the number under 25. Thus,
PPBC cases are rising. It is thought that modern childbearing practices contribute to the increased risk for
developing PPBC. We have shown that tumor cells and normal adjacent mammary epithelial cells (MECs) in
PPBC patients exhibit high levels of SEMA7A expression, and SEMA7A expressing tumors are more
metastatic. Thus, we believe that understanding the mechanisms underlying SEMA7A signaling in the
mammary gland will lead to novel insights into aggressive PPBC. Our recent preliminary data reveal
SEMA7A+ live MECs during postpartum involution suggesting that SEMA7A may promotes cell survival during
postpartum glandular regression. Consistent with our hypothesis, SEMA7A promotes cell survival in cultured
MECs and our preliminary data suggest a reduction in MECs, as well as lymphatic endothelial cells (LECs) and
immune cell populations, in SEMA7A-/- (KO) mice. Additional data from KO mice reveal a decrease in
programmed death ligand-1 (PD-L1+), a molecule that we have shown to be important for immunosuppression
during involution, on mammary macrophages, LECs and MECs. As the epithelial cell apoptosis that occurs
during involution likely results in presentation of self-antigens, an immune-tolerant tissue microenvironment
may be necessary to prevent activation of the immune system by self-antigens and to simultaneously support
survival of remaining cells in the mammary and stromal compartments. Our overarching hypothesis is that
SEMA7A expression promotes cell survival and a transiently tolerant microenvironment in the
mammary gland; furthermore, aberrant sustained upregulation of SEMA7A may pre-dispose women to
breast malignancy. Aim1 will define the role of SEMA7A in epithelial cell survival during mammary gland
involution. Aim2 will decipher SEMA7A mediated mechanisms of immune tolerance in the mammary
microenvironment during postpartum involution. Relevance: To establish clinical relevance, we will also
perform multi-color immunostaining on normal mammary tissues from recently lactating women.

## Key facts

- **NIH application ID:** 10709657
- **Project number:** 5R01HD108335-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Traci Lyons
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $401,885
- **Award type:** 5
- **Project period:** 2022-09-22 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10709657

## Citation

> US National Institutes of Health, RePORTER application 10709657, SEMA7A in postpartum mammary gland development and cellular transformation (5R01HD108335-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10709657. Licensed CC0.

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