Nuclear ErbB-2 as a novel player in triple negative breast cancer

CHERVO MARÍA F., IZZO FRANCO, VENTURUTTI LEANDRO, CHIAUZZI VIOLETA, PROIETTI CECILIA J., GUZMÁN PABLO, ROA JUAN C., CHARREAU EDUARDO H., SCHILLACI ROXANA, CORDO RUSSO ROSALÍA I., ELIZALDE PATRICIA V

Congreso; 6th International PacRim Breast and Prostate Cancer Meeting,; 2015

Triple negative breast cancer (TNBC) refers to the group of tumors with poor prognosis without clinically significant levels of estrogen and progesterone receptors, and which lack membrane ErbB-2 (MErbB-2) overexpression or gene amplification. ErbB-2/HER2 receptor tyrosine kinase is a key player in breast cancer (BC). The dogma of ErbB-2 action has been challenged by the demonstration that MErbB-2 migrates to the nucleus of BC cells where it acts as a transcription factor. We demonstrated that nuclear ErbB-2 (NErbB-2) acts also as a transcriptional coactivator of the signal transducer and activator of transcription 3 (Stat3) to modulate BC growth (1). Here, we explored NErbB-2 presence in TNBC using immunofluorescence (IF) and confocal microscopy. We found a striking NErbB-2 presence in TN MDA-MB-468, MDA-MB-231, and MDA-MB-453 cells, which belong to different TNBC subtypes (2). We also detected NErbB-2 in TNBC tumors. In accordance with previous findings (3), we observed Stat3 nuclear localization in TNBC cells. Notably, we also found a strong nuclear colocalization of ErbB-2 and Stat3. To explore NErbB-2 role in TNBC proliferation, cells were transfected with the ErbB-2-deltaNLS mutant, which is unable to translocate to the nucleus and acts as dominant negative inhibitor of endogenous NErbB-2 translocation (1,4). Our present findings revealed that transfection of ErbB-2-deltaNLS abolished NErbB-2 presence and proliferation in a series of TNBC cell lines, thus demonstrating that NErbB2 is a major proliferation driver in TNBC. The clinical significance of NErbB-2 was assessed in tissue microarrays from a small cohort of 226 primary invasive breast carcinomas by IF. Among them, 51 (23%) were TNBC. Our results revealed NErbB-2 positivity as a significant predictor of worse overall survival in TNBC patients (p=0.045). These findings for the first time reveal NErbB-2 presence and function in TNBC and highlight NErbB-2 as a novel therapeutic target in TNBC.(1) Béguelin W et al., Mol Cell Biol 2010; 30 (23): 5456-72.(2) Lehmann BD et al., J Clin Invest 2011; 121:2750-2767.(3) Lee HJ et al., Carcinogenesis 2011; 32:804-811.(4) Cordo Russo RI et al., Oncogene 2014; Sep 1;0. doi: 10.1038/onc.2014.272