Journal Article

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

Justin Cidado, Brian G. Blair, Sarah Croessmann, Rob Scharpf, Karen Cravero, Grace M. Wang, Rory L. Cochran, Julia A. Beaver, D. Marc Rosen, Hong Yuen Wong, Daniel J. Zabransky, Josh Lauring, Abde M. Abukhdeir, Ashley Cimino-Mathews, Joseph P. Garay, Bracha Erlanger, Morassa Mohseni, Paula J. Hurley, Pedram Argani, Ben Ho Park

2014

Overview

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. Significance Despite the widespread use and success of tamoxifen for treating ER-positive breast cancers, overcoming resistance to this drug remains an unmet need in clinical breast oncology. The results presented in this study demonstrate that overexpression of a novel gene, MACROD2 , can mediate tamoxifen resistance and estrogen independent growth in human breast cancers, and that amplification of MACROD2 in primary breast tumors is associated with worse overall survival.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Base Sequence / Biological Sciences / Breast cancer / breast neoplasms / Breast Neoplasms - metabolism / Cell Line, Tumor / Cell Proliferation / DNA Repair Enzymes - metabolism / Drug resistance / Drug Resistance, Neoplasm / Epigenesis, Genetic / Estrogens / Estrogens - metabolism / Female / Gene Deletion / Gene Dosage / Gene expression / gene overexpression / genes / human growth / Humans / Hydrolases - metabolism / Metastasis / Molecular Sequence Data / Neoplasm Transplantation / Phenotype / Prescription drugs / Prognosis / Receptors, Estrogen - metabolism / RNA Interference / RNA, Small Interfering - metabolism / tamoxifen / Tamoxifen - pharmacology / Transgenes / Treatment Outcome