Loss of Cell Identity as a Prerequisite for Breast Cancer Development

ABSTRACT Transcription Factor (TF) networks are critical in suppressing cancer development by maintaining cell identity. TF networks are hierarchically organized, with pioneer TFs being critical to cell identity by defining cell type- specific cistromes. Not surprisingly, the (epi)genetic damage that accumulates during cancer development, including deregulation of pioneer TFs, corrupts TF network function and compromises cell identity. Damaged cells at risk of transformation can undergo senescence, a tumor suppressor mechanism characterized by a stable proliferative arrest and a senescence-associated secretory phenotype (SASP). While senescence blocks proliferation of damaged cells, senescent cells can facilitate cancer development through cell autonomous and cell non-autonomous mechanisms. As such, senescent cells are an attractive target for anti-cancer therapies. Transcription Factor AP-2 gamma (TFAP2C) is a pioneer TF that specifies the mammary luminal epithelial fate. Deregulation of TFAP2C is frequently observed in breast cancer, leads to increased plasticity, and is associated with reduced survival. This evidence suggests that TFAP2C deregulation facilitates breast cancer development by disrupting cell identity. The epigenomic reorganization required to favor protumorigenic gene expression and the existence of intermediate senescence states arising from TFAP2C deregulation during cancer development, however, remain unknown. We previously revealed the oncogene-induced senescence (OIS) TF network and identified TFAP2C as a TF that plays context-dependent roles in homeostasis and OIS. In homeostasis, TFAP2C facilitates cell type-specific transcription, while upon OIS TFAP2C controls the expression of SASP genes. Surprisingly, downregulation of TFAP2C in fibroblasts and human epithelial mammary cells (HMECs) leads to a senescence state with increased plasticity. Based on these collective data, I hypothesize that deregulation of TFAP2C disrupts cell identity by corrupting TF network function, leading to a transitional senescent state that is conducive to cancer. To test this hypothesis, I will i) generate and modulate TFAP2C networks during OIS in HMECs, ii) identify the functional consequences of TFAP2C deregulation on cell identity, and iii) identify and characterize senescent cells arising from TFAP2C disruption in vivo. This study will provide critical insights into the reorganization of TF networks during cancer progression, the first in vivo evidence of a senescence state arising from disruption of a pioneer TF and reveal therapeutically exploitable liabilities in breast cancers with TFAP2C deregulation. My career goal is to become an independent investigator focusing on the biology of TF networks. To this end, I designed a rigorous K22 program that includes the consultancies of experts in breast cancer, cellular reprogramming and genome editing, attendance to dedicated conferences and career development courses, and an Advisory Committee that will monitor my progress. The career development plan will take place at Rutgers New Jersey Medical School (NJMS), which provides an excellent environment for the development of young investigators through its state-of-the-art facilities, research and administrative support.