MYC and Prostate Cancer

Abstract

Prostate cancer, the majority of which is adenocarcinoma, is the most common epithelial cancer affecting a majority of elderly men in Western nations. Its manifestation, however, varies from clinically asymptomatic insidious neoplasms that progress slowly and do not threaten life to one that is highly aggressive with a propensity for metastatic spread and lethality if not treated in time. A number of somatic genetic and epigenetic alterations occur in prostate cancer cells. Some of these changes, such as loss of the tumor suppressors PTEN and p53, are linked to disease progression. Others, such as ETS gene fusions, appear to be linked more with early phases of the disease, such as invasion. Alterations in chromosome 8q24 in the region of MYC have also been linked to disease aggressiveness for many years. However, a number of recent studies in human tissues have indicated that MYC appears to be activated at the earliest phases of prostate cancer (e.g., in tumor-initiating cells) in prostatic intraepithelial neoplasia, a key precursor lesion to invasive prostatic adenocarcinoma. The initiation and early progression of prostate cancer can be recapitulated in genetically engineered mouse models, permitting a richer understanding of the cause and effects of loss of tumor suppressors and activation of MYC. The combination of studies using human tissues and mouse models paints an emerging molecular picture of prostate cancer development and early progression. This picture reveals that MYC contributes to disease initiation and progression by stimulating an embryonic stem cell-like signature characterized by an enrichment of genes involved in ribosome biogenesis and by repressing differentiation. These insights pave the way to potential novel therapeutic concepts based on MYC biology.

Keywords: prostate cancer; prostatic intraepithelial neoplasia; tumor initiating cells.

Figure 1.

Photomicrographs from Lo-MYC mouse at 4 weeks of age. (A) H&E showing 2 populations of acini. Left shows normal histology; right shows high-grade PIN. (B) Immunohistochemical staining for MYC shows that morphologically transformed cells all stain positively. (C) Prostatic intraepithelial neoplasia cells show reduced Nkx3.1 protein staining. 200x.

Figure 2.

Photomicrograph comparing normal (A) and Lo-MYC (B) mouse prostate. Arrows indicate nucleoli. Note nuclear enlargement and marked enlargement of nucleoli in Lo-MYC mouse, as compared to age-matched wild-type mouse. 600x.