The formation of metastasis is the most common cause of breast cancer-related death among women worldwide. A hallmark event in the dissemination of tumor cells from the primary tumor is the loss of cell-cell adhesion. Normally, epithelial integrity is controlled by the adherens junction (AJ), a membrane-tethered structure consisting of E-cadherin and its associated catenins αE-catenin, β-catenin and p120-catenin (p120). Loss of E-cadherin, which results in inactivation of the AJ, is strongly linked to tumor progression. However, little is known about the underlying mechanisms that drive tumor invasion and metastasis.
Since p120-catenin (p120) controls E-cadherin turnover at the cell membrane, we investigated the possible tumor suppressor functions of p120 in breast cancer. First, we analyzed a comprehensive set of invasive breast cancers using immunohistochemistry, and observed a lack of p120 protein expression in 33% (97/296). Next, we used a conditional mouse model of noninvasive (p53-driven) mammary carcinoma and introduced a conditional p120 allele. Combined loss of p120 and p53 resulted in tumors that resembled human metaplastic breast cancer and metastasize to lungs and lymph nodes. Knockdown of p120 in in anchorage-dependent breast cancer cell lines induces anoikis resistance by increasing sensitivity to growth factors. Interestingly, we observed secretion of inflammatory cytokines upon knockdown of p120. These cytokines likely underlie the formation of the prometastatic microenvironment in p120 negative mammary carcinomas, which in turn facilitate the production of growth factors. Finally, we performed RNA sequencing on p120-ablated cells and uncovered several highly up regulated growth factor receptors, which we will further examine to determine their eligibility as targets for intervention strategies to better treat p120-negative metastatic breast cancers.
Citation Format: Ron C.J. Schackmann, Sjoerd Klarenbeek, Eva J. Vlug, Suzan Stelloo, Miranda van Amersfoort, Milou Tenhagen, Tanya M. Braumuller, Jeroen F. Vermeulen, Petra van der Groep, Ton Peeters, Elsken van der Wall, Paul J. van Diest, Jos Jonkers, Patrick W.B. Derksen. Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A52.