Abstract 342: Silencing of IGF1R induces mesenchymal-to-epithelial transition and inhibits the metastatic properties of triple negative breast cancer cells

Abstract

Abstract Next to skin cancer, breast cancer is the second most common cancer diagnosed among American women and affects nearly 1.3 million women worldwide each year. Aggressive, metastatic disease is directly responsible for the majority of breast cancer-related deaths. Breast tumors lacking expression of three receptors, estrogen receptor (ER), progesterone receptor (PR), and HER2, are commonly referred to as triple negative breast cancers (TNBCs) and make up 15-20% of all diagnosed breast cancers cases. Disparities exist in terms of survival following diagnosis of TNBC, and a devastating reality is that this diagnosis is highly correlated with incurable, metastatic disease. Despite tremendous advantages in treatments for hormone-sensitive breast tumors, a significant number of women with TNBC experience disease progression due to the unavailability of targeted therapies. Insulin-like growth factor-1 receptor (IGF1R) plays a role in breast cancer proliferation, adhesion, invasion, and migration. Overexpression of IGF1R has been noted in 50% of primary breast tumors and in nearly 65% of TNBCs. Consequently, high IGF1R expression in breast cancers correlates well with, high tumor grade, shorter disease-free survival, and poor prognosis. We report the in vitro effects of IGF1R inhibition on the metastatic properties of mesenchymal TNBC cells lines using two methods: (1) shRNA lentiviral system and (2) picropodophyllin (PPP), an IGF1R tyrosine kinase inhibitor. Stably transfected mesenchymal TNBC cells showed down-regulation of IGF1R protein levels, which resulted in mesenchymal-epithelial-transition (MET), as confirmed by up-regulation of epithelial marker, E-cadherin, and down-regulation of mesenchymal marker, vimentin. Importantly, this MET was accompanied by reduced colony formation, cell motility, and invasion. Cell survival assays and fluorescence-activated cell sorting (FACS) analysis revealed that PPP also effectively decreased cell viability and induced cell death, respectively, in TNBC cells. Furthermore, PPP dramatically inhibited cell invasion and migration. Our findings indicate that inhibitors of IGF1R exhibit promising anti-cancer activity in TNBC cells of mesenchymal origin by triggering MET, inducing cell death, and reducing invasive and metastatic properties. Given the very poor outcomes for patients with metastatic TNBCs, we believe the use of IGF1R inhibitors warrant further investigation as prospective anti-cancer options for treating a subset of mesenchymal TN breast carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 342. doi:1538-7445.AM2012-342