MicroRNA Regulation of Stem Cell Signaling in Breast Cancer

Abstract

Several major challenges currently facing breast cancer research include how to prevent malignant progression, disease recurrence, and metastasis. The cancer stem cell hypothesis argues for existence within tumors of small subpopulations of cancer cells driving tumor growth, capable of self-renewal, and responsible for drug-resistance and recurrence. Subpopulations within heterogeneous breast tumors have been identified that are highly tumorigenic, capable of self-renewal, and that possess drug-resistant characteristics. Extensive study of this subpopulation has revealed new details concerning tumorigenesis and drug resistance, however, little is known concerning possible microRNA regulation of these breast cancer stem cells. Many microRNAs are dysregulated in breast cancer where they contribute to tumorigenesis via numerous pathways. Our hypothesis is that dysregulation of miRs in breast cancer cells directly impacts stem cell signaling pathways in cancer stem cells. One important caveat regarding breast cancer stem cell regulation, we believe that this population is dynamic and may possess stage and subtype-specific functions in tumors. We begin our study investigating a relatively unexplored area, the role of cancer stem cells in early stage pre-malignant breast lesions. The biology underlying malignant progression of Ductal Carcinoma In Situ to Invasive Ductal Carcinoma is poorly understood. Here we shed light on the role of microRNA dysregulation and stem cell signaling in DCIS lesions. We have isolated and characterized a cancer stem cell population in a basal-like model of DCIS that we predict serves as malignant precursor cells. Next, we have identified microRNA dysregulation involved in hijacking stem cell signaling in DCIS cells. Finally, we have tested a chemopreventive strategy for targeting DCIS stem cells in vivo. In addition to exploring microRNA regulation of stem cell signaling in early stage breast cancers, we also examined the role of microRNA signaling in invasive tumors. Here, we demonstrated how microRNA dysregulation can impact downstream stem cell factors and self-renewal. The final area we explore is the relationship between cancer stem cells and epithelial to mesenchymal transition to probe the importance of cancer stem cells in tumor dissemination. We examine microRNA dysregulation following EMT in mammary epithelial cells that connects EMT and cancer stem cell renewal.