Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression.

Transcription factors critical for the transition of normal breast epithelium to ductal carcinoma in situ (DCIS) and invasive breast cancer are not clearly defined. Here, we report that the expression of a subset of YAP-activated and YAP-repressed genes in normal mammary and early-stage breast cancer cells is dependent on the nuclear co-activator AIB1. Gene expression, sequential ChIP, and ChIP-seq analyses show that AIB1 and YAP converge upon TEAD for transcriptional activation and repression. We find that AIB1-YAP repression of genes at the 1q21.3 locus is mediated by AIB1-dependent recruitment of ANCO1, a tumor suppressor whose expression is progressively lost during breast cancer progression. Reducing ANCO1 reverts AIB1-YAP-dependent repression, increases cell size, and enhances YAP-driven aberrant 3D growth. Loss of endogenous ANCO1 occurs during DCIS xenograft progression, a pattern associated with poor prognosis in human breast cancer. We conclude that increased expression of AIB1-YAP co-activated targets coupled with a loss of normal ANCO1 repression is critical to patterns of gene expression that mediate malignant progression of early-stage breast cancer.