The Michael M. Shen Lab - Research Interests

Role of Nkx3.1 in prostate carcinogenesis:
In collaborative studies with Cory Abate-Shen's group, we have focused on the Nkx3.1 homeobox gene, which is of interest because of its restricted expression in the developing and adult prostate and its essential role in prostate differentiation and function in mice. The relevance of NKX3.1 for human prostate cancer has been suggested by its localization to chromosomal region 8p21, which undergoes loss-of-heterozygosity (LOH) in approximately 80% of prostate cancers and at high frequency in prostate intraepithelial neoplasia (PIN). We have found that loss-of-function of Nkx3.1 in mice results in histopathological defects that strikingly resemble PIN lesions in humans, consistent with a role in prostate cancer initiation. These and related studies support our model that Nkx3.1 corresponds to a prostate-specific tumor suppressor that undergoes epigenetic inactivation through loss of protein expression. Prostatic intraepithelial neoplasia (PIN) in aged Nkx3.1 mutant mice. Cancer Res. 62: 2999-3004 (2002)

Prostatic intraepithelial neoplasia (PIN) in aged Nkx3.1 mutant mice. Cancer Res. 62: 2999-3004 (2002)

In subsequent studies, we have investigated the potential synergy of loss-of-function of Nkx3.1 and other tumor suppressor genes, such as Pten, which maps to 10q23, a region that undergoes LOH in advanced prostate cancer. We have shown that loss-of-function of Nkx3.1 and Pten cooperate in prostate carcinogenesis, resulting in the synergistic activation of Akt (protein kinase B). We have investigated the malignant potential of the high-grade PIN lesions that form in Nkx3.1^+/-; Pten^+/- compound mutant mice, and have demonstrated their neoplastic progression in a serial transplantation/tissue recombination assay. Furthermore, we have found that a majority of Nkx3.1^+/-; Pten^+/- mice greater than one year of age develop invasive adenocarcinoma, which is frequently accompanied by metastases to lymph nodes, and have observed androgen-independence of high-grade PIN lesions following androgen ablation of
Nkx3.1^+/-; Pten^+/- mice. We conclude that Nkx3.1^+/-; Pten^+/- mice recapitulate key features of advanced prostate cancer, and represent a useful model for investigating associated molecular mechanisms and for evaluating therapeutic approaches.

Lymph node metastases in aged Nkx3.1; Pten mutant mice. Cancer Res. 63: 3886-3890 (2003)

Ongoing studies:
In current work, we are focusing on the molecular analysis of metastatic prostate cancer, using tissue-specific and inducible conditional targeting approaches to provide spatial and temporal regulation of cancer progression. We are also developing methods for incorporating multimodal imaging reporters to allow the use of whole-animal imaging methodologies for longitudinal studies of lineage-marked metastatic growth and spread (in collaboration with Simon Cherry, UC Davis School of Medicine). These approaches will be coupled with expression profiling studies of metastatic prostate cancer, which will eventually become integrated with the analyses of data sets for normal prostate and other stages of prostate cancer progression that are being analyzed in collaboration with Bruce Aronow (U. Cincinnati Medical School) and Cory Abate-Shen. Overall, we envision that increasingly sophisticated genetic manipulations in vivo will provide greatly enhanced as well as novel abilities to pursue the in-depth investigation of the molecular mechanisms underlying progression to metastasis.