Abstract 1076: Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer

Background: The majority of all breast cancers (BC) are estrogen receptor positive (ER+). While ER-targeting endocrine therapies have improved patient survival, many tumors become drug resistant and recur within 20 years. Thus, novel targets are needed to treat recurrent ER+BC. Previous reports have described tumor-promotional effects of Semaphorin 7A (SEMA7A) in ER- disease; however, the role of SEMA7A in ER+ disease is not well-characterized. Hypothesis: SEMA7A promotes cell survival and drug resistance in ER+ BC. Methods: We measured expression of SEMA7A in drug resistant cells via immunoblotting. We then overexpressed SEMA7A and used ER-targeting drugs (fulvestrant and tamoxifen) to test how SEMA7A-expressing cells respond to endocrine therapy. In vitro, we utilized cell proliferation and survival assays. In vivo, we implanted ER+ BC cells, then treated the animals with fulvestrant to assess how SEMA7A affects primary tumor volume and metastasis. We also measured markers of “stemness” and multi-drug resistance via flow cytometry. Results: We found that SEMA7A expression correlated with decreased relapse free survival in patients who received endocrine therapy for ER+BC (Kmplotter; p=0.042). We also observe that SEMA7A can be hormonally regulated in ER+BC, but expression did not consistently decrease with endocrine therapy. Instead, long term estrogen deprivation and ER-targeting treatments increased SEMA7A expression, likely through signaling via other hormone receptors such as the androgen receptor, which also increases with long term estrogen deprivation. Additionally, overexpression of SEMA7A promoted in vitro growth and survival of ER+ cells during estrogen-deprivation, tamoxifen, or fulvestrant treatments. In vivo, SEMA7A promoted fulvestrant resistance in the primary tumor and also induced lung metastases. Finally, we identified pro-survival signaling as a therapeutic vulnerability of ER+SEMA7A+ tumors. Conclusion: These studies show that SEMA7A can promote drug resistance in ER+ BC. We suggest that targeting pro-survival signaling may prove efficacious for treating SEMA7A+ tumors, which are less likely be resistant to endocrine therapies. Citation Format: Lyndsey S. Crump, Garhett L. Wyatt, Taylor R. Rutherford, Jennifer K. Richer, Weston W. Porter, Traci R. Lyons. Hormonal regulation of SEMA7A promotes therapeutic resistance in ER+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 202