Abstract 5135: A chromatin modifier from the 8p11 amplicon in luminal breast cancer

Abstract

Abstract The chromosome 8p11-p12 amplicon is present in 12-15% of breast cancers, resulting in an increase in both copy number and expression of several chromatin modifiers in these tumors, including KAT6A, WHSC1L1, and ASH2L. Previous analyses in SUM52 breast cancer cells showed amplification and over-expression of KAT6A, and subsequent RNAi screening identified KAT6A as a potential driving oncogene. Also known as MYST3, KAT6A is a histone acetyltransferase (HAT) with intrinsic HAT activity towards itself and lysine residues on histone 2B, histone 3, and histone 4. Previously identified as a fusion partner with CREB binding protein (CREBBP) in acute myeloid leukemia, KAT6A is amplified in 8.7% of invasive breast cancers according to the Cancer Genome Atlas (TCGA). Knockdown of KAT6A with several shRNAs in SUM52 cells, a luminal breast cancer cell line harboring the 8p11 amplicon, resulted in reduced growth rate compared to non-silencing controls and profound loss of clonogenic capacity both in mono-layer and in soft agar. The normal cell line MCF10A, however, did not exhibit slower growth with knockdown of KAT6A, nor did other breast cancer cell lines without KAT6A amplfied. Interestingly, SUM52 cells with KAT6A knockdown formed fewer mammospheres in culture compared to non-silencing controls, suggesting a possible role for KAT6A in breast cancer stem cell activity and self-renewal. Further analysis of cell surface markers CD24 and CD44 in KAT6A knockdown cells revealed an increase in cells double positive for CD24 and CD44 expression, a characteristic of increased cell differentiation. Previous work from our laboratory identified FGFR2 as a driving oncogene in SUM52 cells. While FGFR inhibition can completely arrest the growth of these cells, it is completely reversible. Thus, exposure of SUM52 cells to FGFR inhibitors does not significantly affect the colony forming ability of the cells. By contrast, the colony forming efficiency of SUM52 KAT6A knockdown cells in the presence of the FGFR inhibitor PD170374 was significantly reduced compared to cells with KAT6A knockdown only. These data suggest that KAT6A may be a potential novel oncogene in breast cancers bearing the 8p11 amplicon and that it interacts with FGFR2 to regulate expression of transformed phenotypes. While there are other putative oncogenes in the amplicon, the identification of KAT6A as a driving oncogene suggests that chromatin-modifying enzymes are a key class of oncogenes in these cancers, and play an important role in the selection of this amplicon in luminal B breast cancers. Citation Format: Brittany Turner Ivey, Steve Guest, Stephen P. Ethier. A chromatin modifier from the 8p11 amplicon in luminal breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5135. doi:10.1158/1538-7445.AM2014-5135