LAUSR

Our overall goal is to understand drivers of chemoresistance in triple-negative breast cancer (TNBC) and the mechanisms that contribute to metastatic spread in young women. TNBC is more frequently diagnosed in women aged <40 and confers worse overall and distant-metastatic-free survival. Our lab identified a ß1 integrin-ligand, Semaphorin 7A (SEMA7A), that is increased in TNBC and young women's breast cancer (BC). Our central hypothesis is that SEMA7A is increased in TNBC and signals via ß1-integrin to activate epithelial-to-mesenchymal plasticity (EMP) and chemoresistance. We have incorporated genetically manipulated TNBC cell lines and ex vivo tumor samples to define how SEMA7A expression impacts metastasis and chemoresistance. We have also incorporated our Young Women’s BC Cohort to analyze SEMA7A protein expression in human tumors and mammary epithelial tissue. In this cohort, we found that the normal mammary epithelium and tumors exhibit higher SEMA7A expression in women with postpartum BC, defined as BC diagnosed within 10 years postpartum, who are between 30&39-years-old. This sub-population also has increased tumor-associated lymphatic vessel density, as well as increased lymphovascular invasion and LN involvement. Using a 9-month-old mouse model, which is equivalent to a 35-year-old woman, we have shown that mammary tumor growth and metastasis are increased compared to young 8-week-old mice, which can be mimicked by SEMA7A OE tumors in the young mice; these results suggest that the aged microenvironment can replicate the tumor promotional effects of SEMA7A. Similarly, in orthotopic models, SEMA7A OE cells metastasize more frequently to lymph nodes (LNs) and lungs compared to controls. Additionally, via a tail vein injection, we observe that SEMA7A OE cells survive in circulation, seed the lung, and outgrow faster compared to controls. In vitro, SEMA7A promotes migration and invasion via ß1-integrin signaling. Finally, ex vivo metastatic tumor cells, when compared to parental cells, exhibit evidence of EMP. Namely, prior to dissemination, SEMA7A OE cells are mostly mesenchymal-like. Ex vivo, SEMA7A OE cells from LN metastasis express both epithelial/mesenchymal markers, suggesting a hybrid phenotype and maintenance of an invasive phenotype. Whereas those from the lung are more epithelial, which can be more proliferative. EMP is also known to promote chemoresistance and we have found that SEMA7A OE cells are resistant to caspase-mediated cell death in the presence of paclitaxel, a known chemotherapeutic utilized for TNBC, and have increased activation of pAkt, which can mediate pro-survival phenotypes. Overall, our results suggest that the aged mammary gland and SEMA7A expression can promote metastatic spread and chemoresistance and that these patient populations should be considered for direct and indirect targeting of SEMA7A by novel therapeutics. Citation Format: Kelsey Kines, Sarah Tarullo, Virginia Borges, Traci Lyons. The effect of Semaphorin 7A on breast cancer metastases and chemoresistance in young women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1284.