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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2021-01, Vol.81 (1), p.187-198
• Main Authors: Crump, Lyndsey S, Wyatt, Garhett L, Rutherford, Taylor R, Richer, Jennifer K, Porter, Weston W, Lyons, Traci R
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - metabolism; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Estrogens - pharmacology; Female; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Prognosis; Receptors, Estrogen - metabolism; Semaphorins - genetics; Semaphorins - metabolism; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-1601

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 growth in the presence of estrogen deprivation, tamoxifen, and fulvestrant. , 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.