Abstract 2672: Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling

Abstract

Abstract We seek to further our understanding of normal mammary gland biology and determine how pregnancy associated changes in the mammary gland 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 a 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 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. We have shown that tumor cells and normal adjacent mammary epithelial cells (MECs) in PPBC patients exhibit high levels of semaphorin 7a (SEMA7A) protein 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 data reveal that SEMA7A+ MECs are evident during lactation, decreased during the reversible phase of postpartum mammary gland involution, and peak at involution day three, suggesting that SEMA7A promotes survival cell survival during postpartum glandular regression. Consistent with our hypothesis, we reveal that mammary luminal progenitor cells are decreased in SEMA7A knockout mice and SEMA7A promotes cell survival in cultured MECs. Interestingly, a portion of our SEMA7A KO dams exhibit evidence of lactation failure, suggestive of precocious involution. Thus, we propose that SEMA7A activates pro-survival signaling in MECs during lactation and involution. In support of this we show that exogenous SEMA7A activates pro-survival kinase AKT in a β1-integrin dependent manner. Additionally, we show that sustained signaling by SEMA7A leads to cellular transformation in vivo and in vitro and that SEMA7A KO mice crossed to MMTV-PyMT mice exhibit longer latency, ~250 days compared to 50-100 in controls. Since we also observe that SEMA7A levels in blood correlate with SEMA7A levels in breast cancer patient tumors, our results suggest that SEMA7A is a driver of tumorigenesis that could be safely monitored in postpartum women. Citation Format: Taylor R. Rutherford, Traci R. Lyons. Semaphorin 7a promotes cellular transformation via activation of pro-survival signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2672.