Regulation of Breast Cancer Stem Cell by Tissue Rigidity

Abstract

Abstract : The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies indicate that increasing tissue rigidity promotes breast cancer progression, however the underlying molecular mechanism is largely unknown. Breast cancer stem cells have both long-term self-renewal capacity and the ability to initiate tumors. In this proposal, we hypothesize that tissue rigidity regulates breast cancer stem cell properties and function, therefore assisting breast tumor development and promoting chemoresistance. In the past year, our major findings are the following. 1. We have established two 3D culture systems to mimic the physiological ranges of matrix rigidities from normal mammary gland to breast cancer. 2. We have tested whether increasing matrix stiffness promotes CSC properties. 3. We have established the mammary implantation models and determined the proper dose of LOX inhibitor BAPN to be used in vivo to effectively reduce matrix stiffness. 4. We have found that increasing matrix stiffness promotes Epithelial-Mesenchymal Transition(EMT) in human breast cancer cells and this regulation depends on 1 integrin and the EMT-inducing transcription factor Twist1. 5. Together, these results indicate that increasing matrix stiffness promotes EMT via an integrin and Twist1-dependent pathway to regulate breast cancer stem cell function, thus impacting breast cancer progression.