Abstract 1056: Deregulated HDAC9 expression in breast cancer is associated with basal molecular subtype

Abstract

Abstract Estrogens play a pivotal role in the etiology of breast cancer. Estrogen receptor (ER) activity is finely regulated by various transcriptional regulatory complexes including histone acetyl transferases (HAT) and histone deacetylases (HDACs). Previous studies have underlined the potential role of some HDACs in breast tumor progression and their interactions with estrogen signalling. However, expression of the various class I, II and IV HDACs in breast tumors has not been systematically analysed. In this study, we performed a careful analysis of HDACs 1 to 11 expression in five breast cancer cell lines expressing (MCF7, ZR75, T47D) or not (MDA231, MDA436) ERα. HDAC4, HDAC11 and more strikingly HDAC9 were found to be differentially expressed in ERα+ and ERα- cells. HDAC9 mRNA levels were further measured in a panel of 14 breast tumor cell lines expressing or not ERα and classified as luminal, basal A and basal B. This showed that the difference in HDAC9 expression was more related to the luminal or basal characteristics of the breast tumor cells than to ERα expression, with basal cells harboring significantly higher HDAC9 mRNA levels than luminal ones. Comparison of mRNA levels of total HDAC9 with those of the longest HDAC9 isoforms (variants 1, 4 and 5) and the HDAC9ΔCD isoform, lacking the catalytic deacetylase domain (also known as MITR), showed a similar pattern of distribution among luminal, basal A and basal B cells. In basal cells, HDAC9 overexpression was not linked to gain in HDAC9 gene copy number but mainly to higher rates of gene transcription together with enhanced HDAC9 mRNA stability. Based on cDNA array data, the same differential expression was detected in patients’ tumors as significant higher levels of HDAC9 mRNA were measured in ERα negative and basal breast tumors as compared to ERα expressing and luminal ones respectively, suggesting the biological relevance of the results obtained using breast cancer cell lines. In contrast to luminal cells harboring very low or no detectable levels of HDAC9 protein, a 95 kDa HDAC9 protein isoform was detected in basal breast cancer cells, with a predominant and diffuse nuclear distribution as shown by immunofluorescence. Altogether, our results indicate that class IIa HDAC9 is overexpressed at the mRNA and protein levels in the most agressive breast tumors of basal phenotype. The role of this specific HDAC in breast carcinogenesis and ER signaling will be further analysed and described using mammary tumor cell models harboring HDAC9 overexpression or HDAC9 silencing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1056. doi:1538-7445.AM2012-1056