Further more, USP9X is a deubiquitinase that targets multiple proteins involved in cell growth and survival. Hence, the design of a specific inhibitor that targets the USP9X and Mcl 1 interaction could also be a viable and possibly even a better approach to reducing the impact of chemoresistance in different tumors. Conclusions Our current analyses inhibitor Ponatinib demonstrate in principle that the expression of USP9X, Mcl 1 and Bcl xL contributes to chemoresistance in cancer cells. Promoting Mcl 1 ubi quitination and degradation using USP9X inhibitor sen sitizes tumor cells to various chemotherapies including Bcl 2 Bcl xL inhibitors. Background Despite latest individualized therapies, breast cancer is still with 14% of all estimated deaths in the United States the second leading cause of cancer related death in woman in 2012.
To date, breast cancer is the most fre quently diagnosed cancer in females with over 226. 000 new cases. During the last years, several studies about the role of epigenetic alterations including modifications of the acetylation status of histones in the development of hu man cancer have been published. An increased deacetylation of histones leads to an increased cell pro liferation, cell migration, angiogenesis and invasion by reducing the transcription of tumorsuppressor genes. Until now, eighteen different isoenzymes of histone deacetylases are known which are divided into four subclasses. With respect to carcinogenesis, class 1 HDACs seem to be the most im portant ones. HDAC1, 2 and 3 are expressed in the nu cleus of normal cells and shows, in contrary to the other classes, an ubiquitous expression.
In the last years, the expression of HDACs and its prognostic value has been analyzed in different kinds of human cancers. The prognostic role of class 1 HDACs seems to be dif ferent in various kinds of tumor entities. Among the HDAC inhibitors, which can be categorized based on their structure, suberoylanilide hydroxamic acid was first approved for therapy for cutaneous T cell lymphoma in 2006. The majority of breast cancer shows an over expression of estrogen receptor alpha. The endo crine therapy with first anti estrogens or later aromatase inhibitors was one of the first targeted therapies in breast cancer, but not all of the patients with hormone potential prognostic impact of the expression of these proteins.
Methods Study population and histopathological examination For construction of tissue microarrays, we used formalin fixed paraffin embedded tissue samples from 238 patients with primary invasive breast cancer. The overall survival was defined as the time between first diagnosis and date of death. Most of the clinicopathological Cilengitide data in cluding histolocigal type, tumor size and nodal status were extracted from the pathology reports.