Targeting Nuclear ErbB-2 Function in Triple Negative Breast Cancer

CHERVO MF; IZZO F; DE MARTINO M; VENTURUTTI L; MADERA S; GOMEZ POVIÑA JC; CHIAUZZI VA; PROIETTI CJ; GUZMÁN P; ROA JC; CHARREAU EH; SCHILLACI R; ELIZALDE PV; CORDO RUSSO RI

Boston

Congreso; Endocrine Society 100th Annual Meeting (ENDO 2016); 2016

Endocrine Society

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 major player in the breast cancer (BC) scenario. The dogma of ErbB-2 mechanism of 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). Most recently, we have found that ErbB-2 assembles a transcriptional complex with Stat3 and ErbB-3, another member of the ErbBs family, which revealed the first nuclear function of ErbB-2/ErbB-3 dimer (2). 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, HCC-70, MDA-MB-231, and MDA-MB-453 cells, which belong to different TNBC subtypes (3). We also detected NErbB-2 in TNBC tumors. In accordance with previous findings (4,5), we observed constitutive Stat3 and ErbB-3 nuclear localization in TNBC cells. Notably, we here also found a strong nuclear colocalization of ErbB-2/Stat3 and of ErbB-2/ErbB-3. To explore NErbB-2 role in TNBC proliferation, cells were transfected with the ErbB-2DNLS mutant, which is unable to translocate to the nucleus and acts as dominant negative inhibitor of endogenous NErbB-2 translocation (1,2). Our present findings revealed that transfection of ErbB-2DNLS 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) Cordo Russo RI et al., Oncogene 2015; 34 (26): 3413-28. (3) Lehmann BD et al., J Clin Invest 2011; 121:2750-2767. (4) Lee HJ et al., Carcinogenesis 2011; 32:804-811. (5) Tao R-H et al., J Cell Sci 2008; 121: 3207-17.