Abstract B231: Jab1/Csn5 a new player driving the resistance to Her2-targeted therapies for breast cancer.

Her2 a key member in the epidermal growth factor receptor (EGFR) family, is one of the most dominant oncogenes in breast cancer. It is overexpressed in approximately 25%-30% of human breast cancers, which confers a more aggressive tumor phenotype and is associated with poor prognosis. The most effective FDA-approved therapy targeting Her2 is the monoclonal antibody trastuzumab (Ttzm; Herceptin). Ttzm inhibits Her2 activation and blocks downregulation of PI3K/Akt activities, which ultimately leads to increased expression of the cyclin-dependent kinase inhibitor p27, cell cycle arrest, and/or apoptosis. However, about 75% of Her2-positive breast tumors are or become resistant to Ttzm and experience relapse or disease progression. This suggests that tumors acquire or possess an intrinsic mechanism of resistance that prevents from Her2 inhibition. Therefore, it is important for the clinic to identify novel pathway to overcome the resistance. Clinicians cannot predict which patients with Her2-positive breast cancer will benefit from this treatment. Despite extensive studies, the mechanisms and genes responsible for resistance to trastuzumab (Ttzm) have not been entirely identified. Thus, novel strategies for treating Her2-positive disease are urgently needed. Recent studies have proposed that resistance to Ttzm is related to IGF-1R overexpression, rapid p27 degradation, PTEN loss, and PI3K mutations, but a clear target for modifying its resistance has yet to be identified. The cytostatic effect of Ttzm correlates with downregulation of Akt activity, which ultimately leads to increased expression of the cyclin-dependent kinase inhibitor p27, cell cycle arrest and/or apoptosis. c-Jun activation domain-binding protein 1 (Jab1/Csn5), a novel candidate oncogene that we identified, contributes to the progression of breast carcinoma and is correlated with poor prognosis. Jab1/Csn5 expression is low or absent in normal adults breast tissues, but over-expressed in 50% of primary breast tumor and 90% of metastatic breast cancer and other tumor types (ovarian cancer, pancreatic, non-small-cell lung carcinoma, and non-Hodgkin's lymphomas). Jab1/Csn5 negatively regulates p27 tumor suppressor gene, mediates p27 nuclear-to-cytoplasmic export and degradation. Jab1 levels are inversely associated with p27 expression in vitro and in vivo, which means that its up-regulation may contribute to trastuzumab (Ttzm) resistance by promoting p27 degradation. This study was conducted to investigate the role of Jab1 in modulating trastuzumab (Ttzm) resistance. We hypothesize that overexpression of Jab1 plays a crucial role in resistance to Ttzm through negative regulation of the cell-cycle inhibitor p27. Using molecular approaches and pre-clinical studies we identified the pathway leading to resistance the Ttzm. In this study, we will test a novel paradigm that inhibition of Jab1 expression renders Ttzm-resistant cells sensitive to Ttzm by stabilizing nuclear p27 expression levels. Finally Jab1 could be used as a predictive marker of tumor response to Ttzm, which could assist clinicians in selecting the best treatment modalities for patients with breast cancer Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B231. Citation Format: Thuy T. Vu, Terry J. Shackleford, Qingxiu Zhang, Francisco J. Esteva, Elias Drakos, Ling Tian, Timothy Kute, Aysegul A. Sahin, George Z. Rassidakis, Francois X. Claret. Jab1/Csn5 a new player driving the resistance to Her2-targeted therapies for breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B231.