Journal Article

Loss of BPTF restores estrogen response and suppresses metastasis of mammary tumors

Lewis, Steven M., Callaway, Mackenzie K., Ciccone, Michael F., Ostrander, Julie, Tollkuhn, Jessica, Zhao, Yixin, Pomerantz, William C. K., Anderson, Rebecca, Chen, Chen, Hanasoge Somasundara, Amritha Varshini, Anandan, Dhivyaa, Russo, Suzanne, Yang, Shih-Ting, Siepel, Adam, dos Santos, Camila O., Chatterjee, Deeptiman, Zhao, Chris Z., Trousdell, Marygrace C., Wilkinson, John E., Spector, David L.

2025

Overview

Context-specific epigenetic dependencies, shaped by chromatin remodeling can create exploitable vulnerabilities for cancer therapies that are unique to tissue types and cellular identities. Here, we show that loss of BPTF (Bromodomain PHD Finger Transcription Factor), a core component of the NURF (Nucleosome Remodeling Factor) complex, results in the emergence of estrogen-responsive, tamoxifen-sensitive, Estrogen Receptor alpha (ERα) positive mammary tumors without altering cancer cell state and tumor pathology. Elevated ERα levels in BPTF KO mammary tumor cells are linked with decreased TGF-β activity and limited metastatic spread of mammary tumor cells to the lungs. Loss of ERα is sufficient to restore TGF-β activity and the metastatic potential in BPTF KO tumors. These findings highlight a mechanism through which BPTF regulates tumor development and progression in mammary epithelial cells, offering insights into the interplay between chromatin remodeling, estrogen signaling, and their resultant adjuvant therapeutic potential in breast cancer. BPTF is known to regulate chromatin accessibility and self-renewal in mammary epithelial stem cells. Here, the authors discover that BPTF inhibition delays tumor formation, re-activates ERα expression, increases sensitivity to tamoxifen treatment, and inhibits metastatic development.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/31 / 14/105 / 14/19 / 14/63 / 38 / 38/15 / 38/91 / 631/208/200 / 631/67/68/2486 / 64/60 / Animals / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer therapies / Cell growth / Cell Line, Tumor / Cell self-renewal / Chromatin Assembly and Disassembly / Chromatin remodeling / Endocrine therapy / Epigenetics / Epithelial cells / Epithelium / Estrogen Receptor alpha - genetics / Estrogen Receptor alpha - metabolism / Estrogen receptors / Estrogens / Estrogens - metabolism / Estrogens - pharmacology / Female / Females / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Lung Neoplasms - genetics / Lung Neoplasms - secondary / Lungs / Mammary gland / Medical prognosis / Metastases / Metastasis / Mice / Mice, Knockout / multidisciplinary / Neoplasm Metastasis / Nucleosome remodeling factor / Proteins / Science / Science (multidisciplinary) / Signal Transduction / Statistical analysis / Stem cells / Survival analysis / Tamoxifen / Tamoxifen - pharmacology / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transforming Growth Factor beta - metabolism / Transforming growth factor-b / Tumor cells / Tumorigenesis / Tumors