Hormonal regulation of Semaphorin 7a in ER+ breast cancer drives therapeutic resistance

Abstract

Breast cancer is a leading cause of cancer-associated death in women 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 tumors recur, typically as metastases. 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 cancer. 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 endocrine therapies. Instead, endocrine therapy induces one of two outcomes: either 1) decreases SEMA7A and correlates with a good clinical response or 2) increases SEMA7A and correlates with a poor clinical response. We overexpressed SEMA7A in ER+ cell lines and performed in vitro growth assays in the presence of the ERdegrader 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 immunohistochemical 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.

Postpartum breast cancer progression is driven by semaphorin 7a-mediated invasion and survival

“…Furthermore, in hormone-receptor positive (HR+) BCs both AKT and FN promote tamoxifen resistance 57 – 64 and Semaphorin 4C, which is structurally similar to SEMA7A, drives hormonal-independence in HR+ BCs 65 . Thus, we are also exploring the relationship between SEMA7A expression and tumor progression in ER+ models 66 .…”

Anoikis resistance in mammary epithelial cells is mediated by semaphorin 7a Semaphorin-7A and anoikis resistance

“…Evidence for the latter comes from our studies showing that SEMA7A can affect multiple aspects of the tumor microenvironment including collagen and fibronectin deposition, lymphangiogenesis and macrophage infiltration, as well as neighboring cells such as fibroblasts (40,41). Additionally, we provide evidence that SEMA7A expressing cells upregulate drug resistant cell-surface markers (23) and therefore may not respond to conventional chemotherapy; this, along with our analysis of RFS in a large patient dataset revealing that coexpression of ITGA6 and SEMA7A significantly influences probability of relapse suggests that SEMA7A can not only initiate tumor formation, but also influence clinical outcomes. Future studies will investigate these important questions to identify how to best prevent and treat PPBC and all patients with α6-integrin+SEMA7A+ breast cancers.…”

“…During the irreversible phase, MECs lose contact with the basement membrane, primarily composed of laminin, and die by anoikis. Since anoikis is one of the hallmarks of the irreversible phase of mammary involution, and our lab has published that SEMA7A overexpression in multiple breast cancer cell lines decreases anoikis and, most recently, that SEMA7A expression increases over time when cells are detached from matrix, we predicted that expression of SEMA7A would promote anoikis resistance during the second phase of irreversible involution (13,44). We now also show that treating cells with exogenous SEMA7A can confer resistance to anoikis in cultured human MECs suggesting that SEMA7A may signal to neighboring cells to promote resistance to cell death.…”

“…SEMA7A was first identified for its expression on lymphocytes (7), but has since been shown to exert diverse roles in embryonic neuronal development (8), cell differentiation(9-11), ECM deposition (12,13), various components of the immune system (14)(15)(16)(17), and pathologies including fibrosis (12,18,19) and cancer , (13,16,(20)(21)(22). Though elevated SEMA7A is observed in breast cancer, where it has an established role in promoting tumor cell survival (13,23), the role of SEMA7A in normal MECs has not previously been investigated. SEMA7A is known to signal through 1-integrin in immune cells, neurons, and cancer; 1-integrin also mediates MEC survival during development, in part, via phosphorylation and activation of downstream pro-survival signaling mediated by PI3-kinase and protein kinase B, or Akt (24).…”

Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer

“…Not only was it confirmed that Sema7A expression is a strong biomarker of shorter patient survival, but it was found in association with late recurrence, correlated with resistance to hormonal therapy. Experimental evidence demonstrated the role of Sema7A signaling in conferring resistance to estrogen deprivation and promoting disease progression and metastasis 32 .…”