Abstract 4453: Osteopontin-c mediated drug resistance in breast and ovarian carcinoma cells

Abstract Osteopontin (OPN) has been described as an important gene product mediating resistance to chemotherapeutic drugs. However, the specific roles of each OPN splice variant in mediating chemoresistance should be further investigated. This work aimed to evaluate OPNc expression patterns and its correlations with resistance to doxorubicin (DOX) and cisplatin (CIS) in breast and ovarian tumor cell lines, respectively. We used one breast cancer cell line resistant to DOX (MCF-7 DoxR), and one ovarian cancer cell line resistant to CIS (ACRP) and their corresponding parental cell lines (MCF-7 and A2780). Knockdown of OPNc expression levels has been achieved by transfecting cell lines with specific anti-OPNc phosphothiotate modified DNA oligomers. Cytotoxicity assays have been carried out using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet and clonogenic assays. Gene expression has been assessed by quantitative real time PCR. Our results showed that drug-resistant cells overexpress OPNc and P-glycoprotein (P-gp), when compared to their age matched parental cell lines. After transfecting both MCF-7 DoxR and ACRP resistant cell lines with the anti-OPNc oligomers, we found a significant knockdown of OPNc isoform expression, as well as the expression of P-gp. Moreover, these cells exhibited a significantly increased sensitivity to DOX and CIS, and inhibited cell growth and colony formation (p<0,05). Additionally, the epithelial-plasticity phenotype of both MCF-7 DoxR and ACRP resistant cell lines has been reversed, as well the expression of epithelial-mesenchymal transition (EMT)-related interleukins. Altogether, these data evidence that OPNc overexpression can mediate resistance to these chemotherapeutic drugs, possibly by modulating the expression of P-gp and the EMT phenotype. In summary, our data provide early insights on the role of OPNc isoform as a potential molecular target in cancer. Therapeutic strategies aiming to interfere with this isoform expression are likely to overcome resistance to chemotherapeutic agents. Citation Format: Mariana C. Brum, Isabella S. Guimaräes, Luciana Bueno Ferreira, Letícia B. Rangel, Raquel C. Maia, Gabriela N. de Moraes, Etel R. Gimba. Osteopontin-c mediated drug resistance in breast and ovarian carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4453.