EMT programs and therapeutic resistance of breast cancer stem cells

Jeffrey M. Rosen, Molecular & Cellular Biology and Medicine, Baylor College of Medicine
Monday, June 4, 2012, 11:00 AM to 12:00 PM
Location: 180 Engineering 2, The Simularium
Hosted By Lindsay Hinck, MCD Biology

This is one of two keynote talks for the UCSC CIRM Scholar Research Review Day.

Abstract

We have discovered an intimate relationship between epithelial to mesenchymal transition (EMT), cancer stem cells (CSC), and the claudin-low subtype of breast cancer representing a cell state with aggressive and therapeutic resistant properties. The claudin-low subtype is a recently identified rare molecular subtype of human breast cancer. Like basal-like tumors, these tumors are generally triple-negative (ER, PR, HER2) and important therapeutically as there are currently no targeted agents directed at them. Claudin-low tumors express low levels of tight and adherens junction genes, including claudin 3 and E-cadherin, and high levels of markers associated with EMT, including the EMT inducers Snail, Twist, Zeb1, and Zeb2. These tumors are also enriched in recently published signatures derived from human tumor-initiating cells (TIC) and a sorted population enriched for human mammary stem cells. In claudin-low tumors, miRNAs are also differentially expressed, including low expression of the miR-200 family—previously reported to regulate EMT and stemness. Currently, it is unknown whether the presence of the EMT phenotype is due to intrinsic genetic and epigenetic differences within a population of cells or is a response to extrinsic factors emanating from the tumor microenvironment. However, the resulting intratumoral heterogeneity represents one of the major factors involved in tumor relapse and recurrence. Reactivation of the embryonic EMT program during cancer progression promotes tumor invasion and metastasis. Induction of EMT in epithelial cells results in acquisition of molecular and functional traits of CSCs, such as the ability to self-renew. Studies comparing paired human breast cancer core biopsies before and after chemotherapy demonstrated that CSCs were intrinsically chemoresistant. Moreover, the gene signature from these residual tumors identified the EMT/CSC-enriched claudin-low and metaplastic subtypes. An independently derived core EMT interactome gene expression signature was also associated with these tumor subtypes. Furthermore, post-treatment residual tumors contained a higher fraction of claudin-low cells, also enriched with EMT/CSC properties, consistent with their therapeutic resistance. This work is supported by grant RO1CA148761from the National Cancer Institute.