Abstract 2272: Survivin and acetylated Survivin predict outcome in breast cancer and correlate separately with a basal-like and luminal-type expression profile

Abstract

Abstract Background: Basal-like breast cancer is a highly aggressive breast tumor subtype associated with an adverse prognosis for which biologic therapies are not available. These tumors have a distinct molecular profile characterized by an absence of estrogen receptor expression, absence of HER2 amplification, and positive expression of EGFR and/or cytokeratin (CK) 5/6. The object of this study was to evaluate the expression of the anti-apoptotic protein Survivin in basal-like breast cancer and compare it with other molecular subtypes. Our laboratory recently identified that post-translational modification of Survivin by acetylation (Ac) at Lys-129 regulates its export from the nucleus and therefore its anti-apoptotic function. In an effort to understand the expression profile of Survivin and Ac-Survivin in breast tumors, we developed an antibody to the Ac Lys-129 residue. Methods: 4 μM sections of 238 consecutive grade 3 invasive ductal carcinoma cases, arranged on 15 tissue microarrays were stratified into 67 luminal (ER+), 66 HER2 positive (HER2+), 93 basal-like (ER-, HER2-, CK5/6+ and/or EGFR+), and 12 ER-/HER2-/CK5/6-/EGFR- carcinomas. TMAs were immunostained with a rabbit polyclonal Survivin antibody generated to the Lys-129 acetylated residue, a full-length (FL) rabbit polyclonal Survivin antibody (NB-500-201), or normal rabbit serum control. Tumors were scored semiquantitatively and compared with recurrence-free (RF) and overall survival (OS) and with expression of ER, PR, HER2, CK 5/6, and EGFR. Results: In all breast carcinomas examined, FL-Survivin and Ac-Survivin had a predominantly nuclear localization pattern. Ac-Survivin was also expressed in the nucleus of normal breast epithelium. RF (70%) and OS (90%) for FL-Survivin low tumors was significantly better than for tumors with strong FL-Survivin expression (40% and 70%, respectively) at 10 yrs, p = 0.02. By contrast, strong expression of Ac-Survivin was associated with improved RF (70% vs. 40%) and OS (85% vs. 75%), p = 0.03. Molecular subset analyses showed that FL-Survivin expression was associated with a basal-like expression profile, while Ac-Survivin expression was associated with a luminal-type profile, p <0.001. Conclusions: This is the first study to comprehensively demonstrate Survivin and Ac-Survivin expression in different molecular subtypes of breast cancer. High levels of the FL-Survivin protein are predictive of poor outcome in patients with grade 3 invasive ductal carcinoma and correlate directly with a basal-like phenotype. By contrast, high expression of Ac-Survivin is associated with favorable outcome and preferentially correlates with luminal-type tumors. These data suggest that Survivin has different functions in different types of breast cancer and may be useful as a prognostic marker for these distinct tumor subtypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2272. doi:10.1158/1538-7445.AM2011-2272