Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression
Max H Kushner1, Virginie Ory1, Garrett T Graham1
1Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
Abstract:
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.
Insights
The nuclear co-activator AIB1 and transcription factor YAP regulate breast cancer gene expression. Loss of tumor suppressor ANCO1 promotes malignant progression in early-stage breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The precise transcription factors driving breast cancer progression from normal epithelium to invasive disease remain incompletely understood.
- Understanding these molecular drivers is crucial for developing targeted therapies and improving patient outcomes.
Purpose of the Study:
- To elucidate the role of the nuclear co-activator AIB1 and the transcription factor YAP in regulating gene expression during breast cancer development.
- To investigate the mechanism by which AIB1 and YAP control gene transcription, including the involvement of TEAD and the tumor suppressor ANCO1.
Main Methods:
- Gene expression analysis to identify YAP- and AIB1-dependent genes.
- Sequential Chromatin Immunoprecipitation (ChIP) and ChIP sequencing (ChIP-seq) to map protein-DNA interactions.
- In vitro and in vivo models including DCIS xenografts to study the functional consequences of ANCO1 loss.
Main Results:
- AIB1 and YAP cooperate via TEAD to activate or repress gene transcription in mammary cells.
- AIB1-YAP-mediated repression involves the recruitment of the tumor suppressor ANCO1, whose expression is lost during breast cancer progression.
- Loss of ANCO1 function leads to increased cell size and aberrant YAP-driven 3D growth, mirroring malignant progression.
Conclusions:
- The interplay between AIB1, YAP, and TEAD, along with the loss of ANCO1-mediated repression, is a critical mechanism driving gene expression changes in early-stage breast cancer.
- This molecular pathway is essential for the malignant progression of ductal carcinoma in situ (DCIS) and invasive breast cancer.
- The findings identify a potential therapeutic vulnerability in targeting the AIB1-YAP-ANCO1 axis in breast cancer.
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