Abstract P1-06-01: Histone deacetylase HDAC7 is a putative therapeutic target in invasive lobular carcinoma
Authors: Sikora Matthew J , Oesterreich Steffi 
Published: May 2015

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer, accounting for 10-15% of cases. Though ILC represents a minority of breast cancer patients, ILC affects over 30,000 women annually in the US, making ILC the 6th most common women’s cancer. Despite this incidence, no ILC-specific therapeutic options exist. The majority of ILC are estrogen receptor (ER)-positive (&gt;90%); this and other biomarkers suggest that ILC patients are ideal candidates for endocrine therapy. However, the efficacy of endocrine therapy in ILC is poorly understood since no ILC-specific prospective clinical trial data exist. Recent retrospective analyses suggest that a subset of ILC patients may not benefit from endocrine therapy. Understanding the unique mechanisms of endocrine response and resistance in ILC is critical to improving ILC patient outcomes.

We recently identified estrogen-mediated gene expression specific to the ILC cell lines MDA MB 134VI and SUM44PE. ILC-specific ER target genes were enriched for repression by estrogen. Further, tamoxifen regulated estrogen-repressed genes as an agonist in MDA MB 134VI cells, in parallel with tamoxifen-induced growth. Thus, ER-mediated repression of target genes may be critical in maintaining cell growth and survival. Our laboratory previously identified that ER-mediated gene repression in breast cancer cells is mediated by histone deacetylase 7 (HDAC7). E2-induced repression requires specifically HDAC7, not HDAC1-6/8-10. In a panel of breast cancer cell lines, HDAC7 was most strongly expressed in MDA-MB-134VI cells, the only cell line among the panel derived from an ILC. Increased HDAC7 expression in ILC versus invasive ductal carcinoma (IDC) can also be observed in the Cancer Genome Atlas; mean HDAC7 expression in ER-positive tumors is 2-fold higher in ILC (n=148) versus IDC (n=508) (p&lt;0.0001). We hypothesize that HDAC7 mediates the unique ER-mediated gene repression in ILC cells, and may serve as a novel therapeutic target in conjunction with endocrine therapy for ILC.

To model HDAC7 inhibition, we generated stable cell lines carrying inducible HDAC7 shRNA constructs from MCF-7 (IDC) and MDA MB 134VI (ILC). These lines are being used to examine the effects of HDAC7 depletion on estrogen- and tamoxifen-mediated gene expression, cell proliferation, anoikis resistance, and endocrine resistance. Parallel studies using the class IIa HDAC inhibitor MC1568 are being used as proof-of-principle for using HDAC7-specific inhibitors. Additionally, we identified novel splice variants of HDAC7 in breast cancer cells. Based on the mouse homolog Hdac7, these splice variants may alter the ability of HDAC7 to interact with transcription factors, or change its activity as a transcriptional repressor.

Our observations suggest that HDAC7 may mediate ER-mediate gene repression in ILC cells, which may be necessary for cell proliferation and endocrine resistance in this breast cancer subtype. Preclinical studies using ILC model systems will identify the role of HDAC7 and specific splice variants in controlling ER-driven gene expression. Further studies using HDAC7-specific inhibitors will determine whether targeting HDAC7 in ILC patients can improve endocrine response and inhibit endocrine resistance.

Citation Format: Matthew J Sikora, Steffi Oesterreich. Histone deacetylase HDAC7 is a putative therapeutic target in invasive lobular carcinoma [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-06-01.