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Approximately 70% of all breast cancers are estrogen receptor-positive (ER + breast cancer), and endocrine therapy has improved survival for patients with ER + breast cancer. However, up to half of these tumors recur within 20 years. Recurrent ER + breast cancers develop resistance to endocrine therapy; thus, novel targets are needed to treat recurrent ER + breast cancer. Here we report that semaphorin 7A (SEMA7A) confers significantly decreased patient survival rates in ER + breast cancer. SEMA7A was hormonally regulated in ER + breast cancer, but its expression did not uniformly decrease with antiestrogen treatments. Additionally, overexpression of SEMA7A in ER + cell lines drove increased in vitro growth in the presence of estrogen deprivation, tamoxifen, and fulvestrant. In vivo , SEMA7A conferred primary tumor resistance to fulvestrant and induced lung metastases. Prosurvival signaling was identified as a therapeutic vulnerability of ER + SEMA7A + tumors. We therefore propose that targeting this pathway with inhibitors of survival signaling such as venetoclax may prove efficacious for treating SEMA7A + tumors. SIGNIFICANCE: SEMA7A predicts for and likely contributes to poor response to standard-of-care therapies, suggesting that patients with SEMA7A + ER + tumors may benefit from alternative therapeutic strategies. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/1/187/F1.large.jpg.

Hormonal Regulation of Semaphorin 7a in ER+ Breast Cancer Drives Therapeutic Resistance