Abstract B20: Key intermediate progenitor in luminal prostate epithelial differentiation dictates susceptibility to Myc overexpression and Pten loss in prostate cancer cell of origin

Overexpression of Myc and loss of Pten are very common oncogenic events in prostate cancer. However, why these specific oncogenic events, as opposed to others, are involved in prostate cancer develop remains unclear. While the impact of Myc and Pten on cell proliferation is well-characterized, their role in differentiation and the resulting impact on tumorigenesis is poorly understood. We recently developed an in vitro differentiation model in which basal prostate epithelial cells (PrECs) can be differentiated into secretory luminal cells. Our model offers several advantages, in that it is human-specific and readily manipulated genetically and biochemically; providing a rare opportunity to dissect the specific genetic and biochemical events associated with human PrEC differentiation and determining how it is impacted by specific oncogenic events. Using this model, we tested the hypothesis that overexpression of Myc and loss of Pten induce prostate cancer because their dysregulation impairs differentiation of an intermediate progenitor cell population that marks the tumor cell of origin. Transient induction of both Pten and Myc are required for normal PrEC differentiation. Constitutive Myc overexpression initially accelerates differentiation, but the differentiated cells ultimately die via a p53-independent mechanism. Overexpression of Myc in combination with loss of Pten (Myc+shPten), is required for tumorigenesis because it rescues cell survival and blocks terminal differentiation. We identified the chromatin binding protein, ING4, as a Myc target required for PrEC terminal differentiation. ING4 is lost in over 60% of human prostate tumors and in the Myc+shPten cells, ING4 expression is blocked. Loss of ING4 in Myc overexpressing cells is sufficient to replace loss of Pten; ING4 loss, like Pten loss, is required for tumorigenesis to block terminal differentiation and keep cells alive. We further identified Miz1, a component of the Myc repressor complex, as a direct target of ING4 required for terminal PrEC differentiation. Myc/Miz1 is required to suppress integrin α6 and β1 expression during terminal PrEC differentiation; in Myc+shPten cells, Miz1 fails to be induced and integrin α6β1 is aberrantly co-expressed with AR in an intermediate progenitor and tumorigenic cell population. Conclusions: Prostate cancer oncogenesis requires dysregulation of Myc and Pten, because they are required for the normal PrEC terminal differentiation pathway. Pten loss is required to remove the ING4/Miz1-mediated terminal differentiation program initiated by Myc overexpression, to maintain the intermediate progenitor cells in a partially differentiated, yet proliferative state, and to evade cell death. Citation Format: Penny Berger, McLane Watson, Mary Winn, Cindy K. Miranti. Key intermediate progenitor in luminal prostate epithelial differentiation dictates susceptibility to Myc overexpression and Pten loss in prostate cancer cell of origin. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B20.