Despite progress in the treatment of breast cancer, patients with triple-negative breast cancer (TNBC) have limited means for therapy. Since TNBCs do not express HER2, estrogen and progesterone receptors, TNBC patients cannot be treated with Herceptin or endocrine therapy. TNBCs frequently harbor defects in homologous recombination (HR) due to (epi)genetic inactivation of BRCA1, making them sensitive to the clinical PARP1 inhibitor olaparib. However, long-term treatment of BRCA1-deficient mouse mammary tumors with olaparib results in drug resistance. The growing awareness that epithelial-to-mesenchymal transition (EMT) may influence therapy response prompted us to investigate whether olaparib sensitivity of BRCA1-deficient TNBCs is affected by MET, a known EMT inducer that is over-expressed in TNBC and associated with poor survival. For this purpose we have developed a breast cancer GEMM-ESC pipeline, using female GEMM-ESCs derived from our well-validated K14cre;Brca1F/F;Trp53F/F (KB1P) mouse model, of which females spontaneously develop BRCA1-deficient TNBC due to cre-mediated deletion of Brca1 and Trp53 in epithelial tissues. The MET proto-oncogene, was introduced in the Col1a1 locus and resulting KB1P-MET ESCs were injected into blastocysts and good quality chimeras were monitored for mammary tumor formation. Our preliminary data show that BRCA1-deficient mouse mammary tumors with engineered overexpression of MET show accelerated growth, undergo EMT and show intrinsic resistance to olaparib. The underlying mechanisms are, however, unclear. Currently we are studying the impact of EMT-regulators on BRCA1-associated mammary tumorigenesis and assess the contribution of EMT-regulators to olaparib resistance in genetically engineered mouse models of BRCA1-associated breast cancer. Together, these studies will provide novel insights into the roles of EMT regulators in BRCA1-associated breast tumor development, metastasis and therapy resistance.
Citation Format: Martine Van Miltenburg, Jos Jonkers. Epithelial-to-mesenchymal transition and therapy resistance in BRCA1-associated breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3141. doi:10.1158/1538-7445.AM2014-3141