Abstract 5319: BRCA1-IRIS overexpression promotes formation of aggressive breast cancers
Authors: ElShamy Wael M. , Shimizu Yoshiko , Luk Hugh , Horio David , Miron Penelope , Griswold Michael , Iglehart Dirk , Hernandez Brenda , Killeen Jeffrey 
Published: August 2012

Abstract
Introduction: Women with Her2+ or triple negative/basal-like (TN/BL) breast cancers succumb to their cancer rapidly and early in life, due in part to Herceptin resistance that develops in Her2+ patients and because of the lack of appropriate therapies for TN/BL patients. Great effort is being made now to uncover appropriate drug targets to overcome these shortcomings. In this report we examine whether BRCA1-IRIS can be a valuable treatment target for Her2+ and/or TN/BL tumors. Methods: Immunohistochemistry (IHC) staining of breast tumor samples using a newly generated mouse monoclonal anti-BRCA1-IRIS antibody was performed. BRCA1-IRIS expression was correlated to that of AKT1, AKT2, p-AKT, survivin, ER[[Unsupported Character - Symbol Font &#61537;]], PR, and BRCA1/p220 expression detected using commercial antibodies. Where available, patients’ tumor grade, tumor stage, age at diagnosis, and node positivity were also compared. We also generated subcutaneous tumors in SCID mice using human mammary epithelial (HME) cells overexpressing BRCA1-IRIS and then compared AKT and survivin expression, and tumor phenotype and aggressiveness to RasV12-induced tumors. Results: The majority of human breast tumors, especially Her2+ and TN/BL tumors, were BRCA1-IRIS-positive. These tumors also expressed high levels of AKT1, AKT2, p-AKT, and survivin, but were ER[[Unsupported Character - Symbol Font &#61537;]]-, PR-, and BRCA1/p220-negative. BRCA1-IRIS overexpressing Her2+ and TN/BL tumors were high-grade tumors, and showed lymph-node positivity and/or distant metastasis compared to those not overexpressing BRCA1-IRIS. BRCA1-IRIS overexpression also significantly reduced the age at which patients with Her2+ or TN/BL tumors were diagnosed compared to patients with the same tumors but negative for BRCA1/IRIS (51.4±16.2 vs. 64.5±13.2, p≤0.05 for Her2+ and 48.9±10.1 vs. 70.8±6.8, p≤0.01 for TN/BL). Surprisingly, TN/BL/BRCA1-IRIS-positive tumors were larger than Her2+/BRCA1-IRIS-positive tumors (30.6±19.3 vs. 16.1±9.7, p≤0.05). HME cells overexpressing BRCA1-IRIS developed tumors when injected subcutaneously in SCID mice. These tumors were invasive and showed high expression levels of AKT1, AKT2, and p-AKT when compared to RasV12-induced tumors. These tumors also overexpressed the mesenchymal protein vimentin, but did not express the epithelial proteins CK19 and p63, and were BRCA1/p220-negative. In contrast, the less aggressive RasV12-induced tumors expressed CK19, p63, and BRCA1/p220, but not vimentin. Conclusion: These data demonstrate that BRCA1-IRIS overexpression triggers aggressive breast tumor formation, especially in patients with tumors of the Her2+ or TN/BL subtypes. We propose that BRCA1-IRIS inhibition may be used as a novel therapeutic option for the treatment of aggressive breast tumors of the Her2+ and/or TN/BL subtype.
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 5319. doi:1538-7445.AM2012-5319