Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer related mortalities among American men. For advanced prostate cancers, androgen deprivation therapy (ADT) has been the mainstay treatment for nearly 70 years. Malignant relapse of prostate cancer after ADT (commonly referred to as castration-resistant prostate cancer, or CRPC), however, is a significant clinical problem and new strategies are needed to improve patient survival. In contrast to the prostate, cancers arising in the seminal vesicle are exceedingly rare. To identify new genes and signaling pathways involved in prostate cancer initiation and progression we conducted an expression array analyses comparing normal prostate vs. seminal vesicle epithelial cells and identified Sox2 [SRY (sex determining region Y)- box 2] as one of many developmental genes that are highly expressed in adult prostate epithelial cells. Sox2 is an essential transcription factor for maintaining the survival and pluripotency of undifferentiated embryonic stem cells (ESCs), and has an emerging role as an epigenetic reprogramming factor and oncogene. The function of Sox2 in embryonic stem cells is well defined and requires other essential co-factors such as Oct4 and Nanog. In adult prostate tissues and tumors, however, such Sox2 transcriptional co-factors are not expressed, suggesting that Sox2 has unique, non-stem cell gene targets and functions within adult cells. Little is known, however, about the function and clinical impact of Sox2 expression in prostate cancer, and the relationship between Sox2 and the Androgen Receptor (AR) in metastatic, castration-resistant prostate cancer. The long term goal of this project is to elucidate the signaling pathways regulated by Sox2 which can be used to predict cancer progression and can be targeted for the treatment of advanced prostate cancers. The objective of this proposal is to define the mechanism of how Sox2 promotes cell survival and growth in an androgen-deprived environment. Our central hypothesis is that Sox2 functions as an oncogene by regulating a novel set of gene targets to promote cancer cell survival and proliferation, and not via mechanisms of inhibiting differentiation and promoting pluripotency. This mechanism of Sox2 function occurs via interaction with transcriptional co-regulators unique to adult epithelial cells, and not Oct4 or Nanog.
Prostate cancer is the most common non-cutaneous cancer and the second leading cause of cancer related mortalities among American men. The objective of this proposal is to define the mechanism of how the stem cell transcription factor Sox2 promotes cell survival and growth in an androgen-deprived environment.
|Kregel, Steven; Chen, James L; Tom, Westin et al. (2016) Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer. Oncotarget 7:26259-74|
|Reyes, Edwin E; Gillard, Marc; Duggan, Ryan et al. (2015) Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J Transl Sci 1:|
|Kregel, Steven; Szmulewitz, Russell Z; Vander Griend, Donald J (2014) The pluripotency factor Nanog is directly upregulated by the androgen receptor in prostate cancer cells. Prostate 74:1530-43|