Targeting Breast Tumour-Initiating Cells with Vitamin E Analogues

Abstract

Cancer is the second biggest cause of death in the economically developed countries with breast cancer in females and lung cancer in males are the most frequently diagnosed tumours. Clinically referred to as malignant neoplasias, cancer is a combination of patho- logical states, all involving unregulated proliferation of cells in speficic locations. Over the last few years a new concept has emerged, suggesting that cancer is a disease driven by breast tumour-initiating cells (BTICs). Most current anti-cancer therapies used in clinical practice have the capability to reduce the tumour size, however they have detrimental side effects and also fail to target BTICs, a phenomenon that often leads to recurrence of tumours and disease relapse. The novel anti-cancer agents, referred to as mitocans are often selective for cancer cells while being non-toxic to normal cells and may have the propensity to induce apoptosis in tumour-initiator cells including BTICs. Our group has focused on two mitocans, -tocopheryl succinate and its mitochondrially targeted derivative MitoVES. While it has been documented that MitoVES is effective in a variety of cancer cells and in vivo mouse models of cancer, it has not been established what effects it has on BTICs and whether it acts by aiming at relevant molecular targets. The Thesis addresses these questions by establishing three aims, which are addressed in individual chapters. We have validated that the breast cancer cell line MCF7-derived mammospheres (MS) is a valid model to study the BTIC biology and resistance to apoptosis, as both phenotypical and genotypical features confirm increased level of stemness.