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Prostate cancer (PC) is the most frequently diagnosed cancer in Canadian men and is the 3rd cause of cancer mortality. The Androgen Receptor (AR) is activated by androgens (e.g. testosterone), which leads to prostatic cell proliferation. The primary treatment for advanced PC is androgen-deprivation therapy, which is achieved via surgical or chemical castration. Nevertheless, most PC will become castration-resistant (CRPC). Although new anti-androgens (e.g. Enzalutamide) were developed to improve patients’ survival, their efficacy is still very limited and most CRPC patients will die from the disease within a few years. We postulate that by gaining insights into AR signalling networks in the context of CRPC, we could better direct patients towards the best-suited therapy and propose new therapeutic targets. To this aim, we took advantage of an innovative proteomics approach, namely proximity-labeling (BioID), to characterize global AR signalling networks in hormone-dependant LAPC4 cells. We identified 45 AR-associated proteins in non-stimulated cells, 35 of which were not previously reported. Upon androgenic stimulation, the AR signalling network increased to 320 proteins, including 278 (253 were novel) that were restricted to androgen-stimulated cells. Enzalutamide treatment resulted in a loss of 259 proteins from the network when compared to stimulated cells. As expected, this reproduced quite faithfully the status of non-stimulated LAPC4 cells. Interestingly, we identified 4 proteins in the AR network specifically after Enzalutamide treatment. These are interesting targets that may be relevant for the acquisition or the prediction of Enzalutamide resistance. Hence, they could become in time alternative therapeutic targets for CRPC treatment, to be used when Enzalutamide fails. Citation Format: Lauriane VELOT, Dominique Levesque, François-Michel Boisvert, Nicolas Bisson, Frédéric Pouliot. Proteomic identification of therapeutics targets for Enzalutamide resistance in Castration Resistant Prostate Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 220. doi:10.1158/1538-7445.AM2017-220

Metastasis, a fatal complication of breast cancer, does not fully benefit from available therapies. In this study, we investigated whether ATIP3, the major product of 8p22 MTUS1 gene, may be a novel biomarker and therapeutic target for metastatic breast tumors. We show that ATIP3 is a prognostic marker for overall survival among patients with breast cancer. Notably, among metastatic tumors, low ATIP3 levels associate with decreased survival of the patients. By using a well-defined experimental mouse model of cancer metastasis, we show that ATIP3 expression delays the time-course of metastatic progression and limits the number and size of metastases in vivo. In functional studies, ATIP3 silencing increases breast cancer cell migration, whereas ATIP3 expression significantly reduces cell motility and directionality. We report here that ATIP3 is a potent microtubule-stabilizing protein whose depletion increases microtubule dynamics. Our data support the notion that by decreasing microtubule dynamics, ATIP3 controls the ability of microtubule tips to reach the cell cortex during migration, a mechanism that may account for reduced cancer cell motility and metastasis. Of interest, we identify a functional ATIP3 domain that associates with microtubules and recapitulates the effects of ATIP3 on microtubule dynamics, cell proliferation, and migration. Our study is a major step toward the development of new personalized treatments against metastatic breast tumors that have lost ATIP3 expression. Cancer Res; 73(9); 2905–15. ©2013 AACR.