The Role of Dedifferentiation in Basal like Breast Cancer

ABSTRACT The adult mammary gland is maintained by unipotent progenitor populations which are derived from multipotent stem cells exclusive to embryonic development. The emergence of multipotency caused by oncogenic mutations in adult glands is a common process in malignant breast cancer transformation that enables cellular plasticity and promotes tumor heterogeneity. Although these processes pose immense therapeutic challenges for aggressive undifferentiated breast cancers such as Basal-like Breast Cancer (BLBC), the most common Triple Negative Breast Cancer (TNBC), the mechanisms underlying cellular plasticity in the adult mammary gland remain poorly understood. The BLBC founder cell (BFC) is likely of the ER- luminal lineage as suggested by multiple groups, however concrete evidence to prove this notion is lacking. In this proposal, we seek to identify and characterize the BFC and to uncover mechanisms responsible for multipotency reactivation in these cells. We hypothesize that a transformation competent unipotent luminal progenitor acquires multipotency through a conserved pathway or gives rise to multipotent progeny that undergo stepwise reprogramming essential for BLBC tumor progression. To test this hypothesis, I have performed single cell RNA sequencing of hyperplastic mammary glands in the C3/Tag BLBC mouse tumor model to (1) establish candidate BFC populations by integrating epithelial clustering data with RNA velocity and pseudotemporal analysis of cell populations, (2) determine the role of suspected BFC clusters in mammary gland and tumor development, and finally (3) identify the molecular determinants of dedifferentiation in the BFC. Findings from the analysis of this data and from follow up lineage tracing experiments will reveal the BFC in the highest resolution to date as well as pathways involved in its transformation and subsequent dedifferentiation. A detailed understanding of aberrant dedifferentiation in BLBC may be useful for improving the state of current and future BLBC treatments and for treatment of other aggressive cancers that employ cellular plasticity for treatment resistance and evasion. Under the proven mentorship and expertise of Dr. Wenjun Guo, I will execute the research and training plan outlined in this proposal. This, combined with the training environment provided by the Albert Einstein College of Medicine will allow me to contribute to the fields of breast cancer and stem cell biology and to develop the research and professional skills necessary to become an independent physician-scientist.