MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers.

Proceedings of the National Academy of Sciences of the United States of America 2014 Dec 9

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Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.

Citation

Morassa Mohseni, Justin Cidado, Sarah Croessmann, Karen Cravero, Ashley Cimino-Mathews, Hong Yuen Wong, Rob Scharpf, Daniel J Zabransky, Abde M Abukhdeir, Joseph P Garay, Grace M Wang, Julia A Beaver, Rory L Cochran, Brian G Blair, D Marc Rosen, Bracha Erlanger, Pedram Argani, Paula J Hurley, Josh Lauring, Ben Ho Park. MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers. Proceedings of the National Academy of Sciences of the United States of America. 2014 Dec 9;111(49):17606-11