title: Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis.
abstract: Chemoresistance allows for disease to recur and ultimately causes the death of most breast cancer patients. This scenario is particularly relevant in patients harboring triple-negative breast cancer (TNBC) tumors for which there are no effective FDA-approved drugs. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Of these, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to doxorubicin and docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector HIF-1α. Since HIF-1α is a major activator of VEGF-A production, and therefore a stimulator of tumor angiogenesis, loss of HIF-1α in the WAVE3-knockdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1→HIF-1α→VEGF-A signaling axis, and support the possibility that WAVE3 inhibition may be a promising target for TNBC cancer therapy.
authors.affiliation: Department of Molecular Cardiology; Cleveland Clinic Lerner Institute ; Cleveland, OH USA.
authors.forename: Gangarao
authors.initials: G
authors.lastname: Davuluri
authors.affiliation: Case Comprehensive Cancer Center; Case Western Reserve University ; Cleveland, OH USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Schiemann
authors.affiliation: Department of Molecular Cardiology; Cleveland Clinic Lerner Institute ; Cleveland, OH USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.affiliation: Department of Molecular Cardiology; Cleveland Clinic Lerner Institute ; Cleveland, OH USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Sossey-Alaoui
keywords: HIF-1α; STAT1; WAVE3; angiogenesis; apoptosis; chemoresistance; metastasis; triple-negative breast cancer