title: β3 integrin promotes chemoresistance to epirubicin in MDA-MB-231 through repression of the pro-apoptotic protein, BAD.
abstract: Resistance to anthracycline based chemotherapy is a major limitation in the treatment of breast cancer, particularly of the triple negative sub-type that lacks targeted therapies. Resistance that arises from tumor-stromal interaction facilitated by integrins provides the possibility of targeted disruption. In the present study, we demonstrate that integrin β3 signaling inhibits apoptosis induced by a DNA-damaging chemotherapeutic agent, epirubicin, in MDA-MB-231 breast cancer cells. Drug efflux based mechanisms do not contribute to this effect. We show that integrin β3 employs the PI3K-Akt and the MAPK pathway for enabling cell survival and proliferation. Further, our results indicate that integrin β3 helps inhibit epirubicin induced cytotoxicity by repression of the pro-apoptotic protein BAD, thus promoting an anti-apoptotic response. Myristoylated RGT peptide and a monoclonal antibody against integrin β3 brought about a reversal of this effect and chemosensitized the cells. These results identify β3 integrin signaling via repression of BAD as an important survival pathway used by breast cancer cells to evade chemotherapy induced stress.
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Madhumathy G
authors.initials: MG
authors.lastname: Nair
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Krisha
authors.initials: K
authors.lastname: Desai
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Jyothi S
authors.initials: JS
authors.lastname: Prabhu
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: P S
authors.initials: PS
authors.lastname: Hari
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India.
authors.forename: Jose
authors.initials: J
authors.lastname: Remacle
authors.affiliation: Division of Molecular Medicine, St. John's Research Institute, Bangalore, India. Electronic address: tssridhar@sjri.res.in.
authors.forename: T S
authors.initials: TS
authors.lastname: Sridhar
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D039661:Integrin beta3 / Q000378:metabolism*; D008024:Ligands; D019814:Myristic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D039661:Integrin beta3; D008024:Ligands; D051025:bcl-Associated Death Protein; D019814:Myristic Acid; D015251:Epirubicin; D003094:Collagen
keywords: Apoptosis; Breast cancer; Chemoresistance; Epirubicin; Extracellular matrix; Integrin β3