Semaphorin 7a promotes breast tumor progression via cell survival, matrix remodeling, and epithelial to mesenchymal transition

ABSTRACT Young women diagnosed with breast cancer (BC) have poor prognosis due to increased rates of metastasis. Additionally, women within 10 years of most recent child-birth at diagnosis are ～3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum BC (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression. Our published results revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis, all of which are also increased in pre-clinical models of PPBC. However, whether SEMA7A drives progression in PPBC remains largely unexplored. Our results presented herein show that silencing of SEMA7A decreases tumor growth in postpartum hosts while overexpression increases growth in nulliparous hosts. Further, we show that SEMA7A effects multiple pro-tumor attributes such as cell survival, tumor associated COX-2 expression, fibronectin deposition, and fibroblast-mediated collagen deposition in the tumor microenvironment. Finally, we show that co-expression of SEMA7A/COX-2/FN predicts for poor prognosis in breast and ovarian cancer patient cohorts. These studies suggest SEMA7A as a key mediator of BC progression and that targeting SEMA7A may open avenues for novel therapeutic strategies. BRIEF SUMMARYWe identify potential tumor intrinsic and extrinsic roles for SEMA7A in promotion of breast cancer including invasion, modulation of the microenvironment, survival in circulation, and metastasis.