Deciphering Age-Related Prostate Carcinogenesis

yan-150The laboratory of GRU Cancer Center’s Dr. Chunhong Yan is interested in the molecular mechanism behind the development of prostate cancer. Prostate cancer is associated with aging – not only the genetic alterations induced by the aging process, but also with aging-related hormonal changes. While the Yan group’s September 2015 Oncogene publication demonstrated that the stress sensor ATF3 (activating transcription factor 3) functions as a tumor suppressor of prostate cancer induced by Pten loss (a hallmark genetic characteristic of prostate cancer), their November 2015 online publication in the same journal supports a similar tumor suppressor role for ATF3 in hormone-induced prostate cancer. Circulating plasma hormone levels of aging men were mimicked in a mouse model developed previously by the Yan laboratory. Cancer Center researchers Drs. Yan, Ziyan Wang, Yong Teng, Han-Fei Ding, and John K. Cowell and colleagues showed that although these hormones induced intraepithelial neoplastic lesions in the dorsal prostates of only 12% (1 of 8) wild-type mice, 92% (11 of 12) of mice that were deficient in ATF3 developed lesions. The group further showed that hormone treatment of ATF3 knock-out mice resulted in increased epithelial cell proliferation, which they attributed to increased androgen signaling. Additional in vivo and in vitro data suggest that ATF3 deficiency induces the differentiation of basal cells into luminal cells. Dorsal prostates of hormone-treated wild-type (WT) and ATF3 knock-out mice were stained for basal (CK5+) and luminal (CK8+) cells. While 2% of the epithelial cells of WT dorsal prostates were double-stained (CK5+CK8+), more than 20% of ATF3 knock-out prostate epithelial cells were CK5+CK8+, and these were found on top of a layer of CK5+ cells. Using RWPE-1 normal human prostate epithelial cells, the researchers showed a fivefold increase in CK8+ cells upon ATF3 knockdown with siRNA, indicating differentiation from basal to luminal phenotype. Using clinical samples, they also demonstrate that down-regulated expression of ATF3 correlates with human prostate cancer versus normal tissue, as well as with poor relapse-free survival of cancer patients.

[Wang Z, Kim J, Teng Y, Ding H-F, Zhang J, Hai T, Cowell JK, Yan C. Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5+CK8+ epithelial cells. Oncogene advance online publication, 2 November 2015; doi:10.1038/onc.2015.417.]
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Allison Brown
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Written by Allison Brown

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