MYC Overexpression Induces Prostatic Intraepithelial Neoplasia and Loss of Nkx3.1 in Mouse Luminal Epithelial Cells

Abstract

Lo-MYC and Hi-MYC mice develop prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma as a result of MYC overexpression in the mouse prostate[1]. However, prior studies have not determined precisely when, and in which cell types, MYC is induced. Using immunohistochemistry (IHC) to localize MYC expression in Lo-MYC transgenic mice, we show that morphological and molecular alterations characteristic of high grade PIN arise in luminal epithelial cells as soon as MYC overexpression is detected. These changes include increased nuclear and nucleolar size and large scale chromatin remodeling. Mouse PIN cells retained a columnar architecture and abundant cytoplasm and appeared as either a single layer of neoplastic cells or as pseudo-stratified/multilayered structures with open glandular lumina—features highly analogous to human high grade PIN. Also using IHC, we show that the onset of MYC overexpression and PIN development coincided precisely with decreased expression of the homeodomain transcription factor and tumor suppressor, Nkx3.1. Virtually all normal appearing prostate luminal cells expressed high levels of Nkx3.1, but all cells expressing MYC in PIN lesions showed marked reductions in Nkx3.1, implicating MYC as a key factor that represses Nkx3.1 in PIN lesions. To determine the effects of less pronounced overexpression of MYC we generated a new line of mice expressing MYC in the prostate under the transcriptional control of the mouse Nkx3.1 control region. These “Super-Lo-MYC” mice also developed PIN, albeit a less aggressive form. We also identified a histologically defined intermediate step in the progression of mouse PIN into invasive adenocarcinoma. These lesions are characterized by a loss of cell polarity, multi-layering, and cribriform formation, and by a “paradoxical” increase in Nkx3.1 protein. Similar histopathological changes occurred in Hi-MYC mice, albeit with accelerated kinetics. Our results using IHC provide novel insights that support the contention that MYC overexpression is sufficient to transform prostate luminal epithelial cells into PIN cells in vivo. We also identified a novel histopathologically identifiable intermediate step prior to invasion that should facilitate studies of molecular pathway alterations occurring during early progression of prostatic adenocarcinomas.

Molecular genetics of prostate cancer: new prospects for old challenges

“…Consistent with these findings, detailed phenotypic analysis of Probasin-Myc and Nkx3.1-Myc transgenic mouse lines also suggests that PIN and prostate cancer originates from luminal cells (Iwata et al 2010). Notably, CARNs correspond to luminal cells of origin for prostate cancer in mouse models, as evidenced by targeted deletion of Pten resulting in highgrade PIN and invasive carcinoma following androgen repletion and prostate regeneration ).…”

Different Growth Patterns of Canine Prostatic Carcinoma Suggests Different Models of Tumor-Initiating Cells

“…Luminal cells are generally accepted as the cells of origin for human PC 26,29 and human pathologists diagnose the disease based on the absence of basal cell markers. 42 Evidence from the mouse implicates both luminal cells 18,39,41 and basal cells 22,25,38 39 Alternatively, neoplastic transformation may commence in differentiated progenitor cells (intermediate cells) that co-opt self-renewal programs form tissue stem cells. 5 Finally, even mature differentiated postmitotic prostatic luminal cells could be reprogrammed by oncogenic pressure into tumor-initiating cells.…”

Human Epithelial Basal Cells Are Cells of Origin of Prostate Cancer, Independent of CD133 Status

“…Although prostate cancer can arise from luminal (stem) cells [1,2], the concept that basal-enriched stem cells can also be cells of origin of prostate cancer is new and controversial [3,4]. In order to confirm that benign basal cells can be malignantly transformed, we used cells from the initiated but nontumorigenic BPH-1 epithelial cell line [20] that form tumors in recombination with tumor stroma (CAFs) [13].…”

“…In prostate cancer, this arrangement is disrupted, with an associated loss of cells with a basal cell phenotype. A minor luminal stem cell population was shown to be an efficient target for oncogenic transformation in mice [1], although this was not surprising given that mouse models of prostate cancer are commonly induced by luminal-specific promoters, including probasin and/or prostate-specific antigen (PSA) [2]. More surprisingly, murine and human basal epithelial stem cells expressing high Trop2 and CD49f were also susceptible to malignant transformation [3,4].…”