Abstract 2995: MYST2 gene co-amplification in HER2-amplified breast cancer and contribution to therapeutic resistance.
Authors: Gordon Michael A. , Weng Peggy , Press Michael F. 
Published: August 2014

Abstract
HER2 gene amplification is a marker of poor prognosis in breast cancer; the advent of HER2-targeted therapies trastuzumab and lapatinib has improved the survival rates for patients with HER2-positive disease, however not all patients receive benefit from these therapies and there is heterogeneity with respect to disease progression and clinical outcome in this subgroup of breast cancer patients. Previous studies have identified topoisomerase II-alpha to be amplified in a subset of HER2-positive breast cancers and a predictive marker of response to anthracycline treatment. Identifying other HER2 co-amplified genes which have clinical significance will aide in personalizing treatments, thus sparing patients from toxic and ineffective therapies, and will also identify potential new drug targets.
To identify gene candidates, copy number alterations in 50 breast cancer cell lines were evaluated using SNP microarrays and tested for association with HER2 positivity. Copy number data were combined with publicly available gene expression microarray data, and candidate genes that were co-amplified with HER2, overexpresed, and had potential functional significance were identified. A region localized to chromosome 17q21.33 was found to be significantly associated with HER2 positivity.
MYST2 (also called HBO1, KAT7), a histone acetyltransferase with central roles in regulation of DNA replication and gene transcription including transcription of steroid hormone receptor targeted genes, was identified as a potential candidate gene within the 17q21.33 amplicon. MYST2 amplification and expression status was validated in cell lines by dual-color silver in situ hybridization (dSISH) and real-time quantitative PCR. MYST2 was amplified and overexpressed in 10 out of 17 HER2-amplified cell lines and 0 out of 33 HER2-not-amplified cell lines (p&lt;0.001). In a panel of 107 breast tumors, dSISH analysis showed that MYST2 was amplified in 11 of 26 HER2-amplified breast tumors and 1 out of 81 HER2-not-amplified tumors (p&lt;0.001). siRNA-mediated knockdown of MYST2 in MYST2-amplified cell lines BT474 and EFM192A resulted in a decrease in proliferation, accumulation of cells in G0/G1 phase, and increased sensitivity to tamoxifen treatment. Overexpression of MYST2 in MYST2-non-amplified cell lines MCF7 and MDAMB415 resulted in increased growth and decreased sensitivity to tamoxifen treatment. Furthermore, overexpression of a mutated and inactivated version of MYST2 in MCF7 and MDAMB415 caused increased sensitivity to tamoxifen treatment.
In conclusion, MYST2 is co-amplified in a subset of HER2-positive breast cancers, and MYST2 amplification and overexpression may contribute to resistance to tamoxifen treatment. In addition, MYST2 amplification may contribute to aggressive disease behavior and poor prognosis, and is currently being evaluated in a large breast cancer cohort to address these issues.
Citation Format: Michael A. Gordon, Peggy Weng, Michael F. Press. MYST2 gene co-amplification in HER2-amplified breast cancer and contribution to therapeutic resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2995. doi:10.1158/1538-7445.AM2013-2995