| Literature DB >> 25422431 |
Morassa Mohseni1, Justin Cidado1, Sarah Croessmann1, Karen Cravero1, Ashley Cimino-Mathews1, Hong Yuen Wong1, Rob Scharpf1, Daniel J Zabransky1, Abde M Abukhdeir1, Joseph P Garay1, Grace M Wang1, Julia A Beaver1, Rory L Cochran1, Brian G Blair1, D Marc Rosen1, Bracha Erlanger1, Pedram Argani1, Paula J Hurley1, Josh Lauring1, Ben Ho Park2.
Abstract
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.Entities:
Keywords: ER positive; MACROD2; breast cancer; resistance; tamoxifen
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Year: 2014 PMID： 25422431 PMCID： PMC4267353 DOI： 10.1073/pnas.1408650111
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205