A SIM2s/SEMA7A Switch Drives ER+ Breast Cancer Progression - SUMMARY Despite the availability of targeted therapies for estrogen receptor positive (ER+) breast cancers, which comprise over 70% of breast cancers, most breast cancer-related deaths are attributed to recurrent ER+ breast cancer. Thus, there is an unmet need to identify novel targets for treating ER+ patients with metastasis. We have found that levels of Semaphorin 7a (SEMA7A) mRNA, which encodes for a membrane linked protein that can also be shed from the cell, are associated with decreased overall survival (OS) in ER+ breast cancer patients. Furthermore, ER+ patients treated with Tamoxifen exhibit shortened OS if their tumors are SEMA7A high, suggesting that SEMA7A may drive resistance to endocrine therapy resulting in tumor progression and metastasis. We have preliminary data to suggest that SEMA7A overexpression promotes resistance to endocrine therapies via activation of cell survival pathways in breast tumor cells. Additionally, we have shown that ER mediated transcription drives SEMA7A expression and that SEMA7A expressing cells are resistant to ER- and CDK4/6-targeted therapies, yet sensitive to inhibition of survival pathways. We have also discovered that decreasing expression of Singleminded-2s (SIM2s), a transcriptional repressor with known tumor suppressive activities, also results in activation of pro-survival signaling, as well as epithelial to mesenchymal transition (EMT), and resistance to ER-targeted therapy. Together, our preliminary data suggest that SIM2s binds to the SEMA7A promoter and represses SEMA7A transcription. We have also identified that ER+ breast cancers in women diagnosed within 10 years ofa pregnancy are enriched for the highly-proliferative ER+ luminal B subtype, frequently progress to metastatic disease while on endocrine therapy, and that SEMA7A can predict for relapse in this patient population. Thus, we propose that SIM2s mediated repression of SEMA7A may be lost in these postpartum breast cancers (PPBCs). PPBCs also exhibit increased expression of SEMA7A and in programmed cell death ligand-1 (PD-L1) and are sensitive to PD-L1 targeting in pre-clinical studies. Additionally, in TCGA SEMA7A expressingtumors are enriched for makers of immunosuppression including PD-L1, PD-1 and FOXP3. Based on these new results, we propose the hypothesis that a SIM2s/SEMA7A switch mediates ER+ breast cancer progression and metastasis by conferring mechanisms of intrinsic resistance to therapy, EMT and immunosuppression in the TME. To address this hypothesis, we propose three Specific Aims. In Aim 1, we will determine the SIM2s/SEMA7A switch in therapeutic resistance and progression in ER+ breast cancer. In Aim 2, we will definethe role of the SIM2/SEMA7A switch in altering immune suppression via PD-L1 to promote breast cancer progression. In Aim 3 we will analyze the relationship between SIM2s and SEMA7A in women with ER+ breast cancer as predictive factors for metastatic recurrence and resistance to standard therapy. We expect that dissecting the roles of SIM2s and SEMA7A in breast cancer will aide in developing novel therapeutic strategies.
