Breast cancer is leading cause of cancer-associated death in the United States, and approximately 70% of all cases are estrogen receptor positive (ER+). While effective ER-targeting endocrine therapy has substantially progressed the successful treatment of primary ER+ tumors, approximately 20% of these tumors will recur, typically at metastatic sites. Recurrent ER+ tumors consistently develop resistance to endocrine therapies, making them difficult to treat and contributing to patient death. Therefore, novel molecular targets are needed to treat recurrent ER+ breast cancers. Here, we describe semaphorin 7a (SEMA7A) as a driver of tumor growth, recurrence, and metastasis in ER+ breast cancer. SEMA7A is a signaling protein that is overexpressed in ER+ breast cancer, where it confers significantly decreased patient survival rates for patients on endocrine therapy. We show that SEMA7A is hormonally regulated in ER+ breast cancer; yet, SEMA7A expression does not uniformly decrease in patients treated with hormone-targeting endocrine therapies. Instead, anti-endocrine therapy either 1) decreases SEMA7A and correlates with a good clinical response or 2) increases SEMA7A and correlates with a poor clinical response. We therefore overexpressed SEMA7A in ER+ cell lines and performed in vitro growth assays in the presence of the ER-degrader fulvestrant. We also injected these cells into mammary fat pads of NSG mice, and then treated the animals with fulvestrant. Tumors were measured every three days, then harvested for immunohistochemistry analysis. SEMA7A overexpression confers resistance to fulvestrant treatment in vitro and in vivo. Mechanistically, we show that SEMA7A suppresses expression of ER and alters the tumor microenvironment in fulvestrant-treated tumors. These data support SEMA7A as a novel driver of endocrine resistance in ER+ breast cancer. Finally, we identify therapeutic vulnerability of ER+SEMA7A+ tumors and propose that SEMA7A warrants additional investigation in a clinical setting.
