Abstract 2280: A novel c-Myc transgenic model for human cancers

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Androgen-deprivation therapy (ADT) is a standard therapy for advanced and metastatic prostate cancer (PCa). However, most PCa will relapse and become the lethal castration-resistant PCa (CRPC). Chemotherapy such as Docetaxel, only modestly extends patient survival. To overcome castration resistance and chemoresistance, it is crucial to delineate the underlying molecular mechanisms. c-Myc is the most significantly amplified oncogene in human PCa, and its overexpression is very common in PCa as early as PIN. The Hi-Myc model uses an enhanced probasin promoter to drive c-Myc overexpression in prostate epithelia. Hi-Myc mice develop invasive prostate carcinomas that share molecular features with human PCa. However, since the probasin promoter activity is androgen-dependent, Hi-Myc tumors lose c-Myc expression upon castration. Therefore, the tumor regression represents the mixed effects of both an artificial direct effect from loss of c-Myc oncogene expression and a potential real effect from tumor cellular response to androgen-ablation that is relevant to human PCa. Finally, Hi-Myc mice do not develop CRPC tumors. To study CRPC and chemoresistance of CRPC, we have developed a novel transgenic model to express the c-Myc oncogene in Any tissue in an inducible manner (Ai-Myc model). After crossing with PB-Cre4 mice expressing Cre in prostate epithelia, this model allows us to specifically turn on the expression of c-Myc along with Luc2 (an enhanced luciferase for BLI imaging) in prostate. In addition, once turned on, the expression of c-Myc and Luc2 are no longer dependent on androgen. The PB-Cre4/Ai-Myc mice developed early onset of mPIN, but with much delayed prostate tumor progression. Only a fraction of mice developed significant prostate tumors after one-year of age. Since c-Myc oncogene may induce p53 tumor suppressor activation, and loss or mutation of p53 is a frequent event in late-stage human PCa, we further crossed these mice with p53loxP/loxP mice to generate the PB-Cre4/Ai-Myc/p53loxP/loxP model. Loss of p53 greatly enhanced prostate tumor progression; about 40% of mice developed significant prostate tumors within 4-5 months when all mice have to be sacrificed due to the unexpected growth of large tumors of the epididymis, a rare cancer in human. These epididymis tumors are positive for c-Myc and Luc2, confirming the previously reported off-target activity of PB-Cre4 mice. The nature of these epididymis tumors remains to be determined. We are exploring using several approaches, including early castration together with implantation of androgen pellets, to overcome this problem, which will allow us to concisely study the c-Myc signaling pathway in castration response, castration and chemo-resistance of prostate tumors. Finally, different tissue / organ-specific Cre transgenic mouse line will allow our Ai-Myc model to be used to study different types of human cancers and/or other diseases. Citation Format: Wei Wang, Jiangong Ren, Bingning Dong, Michael M. Ittmann, David D. Moore, Feng Yang. A novel c-Myc transgenic model for human cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2280. doi:10.1158/1538-7445.AM2015-2280