Cory Abate-Shen

Professor Department of Neuroscience and Cell Biology UMDNJ-Robert Wood Johnson Medical School Chief Division of Developmental Medicine and Research, Department of Medicine UMDNJ-Robert Wood Johnson Medical School Member Cancer Institute of New Jersey Co-Director Prostate Cancer Program, CINJ Ph.D., 1988, Cornell University Medical College, New York Tel:  [732] 235-5161 Fax: [732] 235-5789 abate@cabm.rutgers.edu

Vertebrate development, homeoproteins, cancer, prostate cancer.

My research is focused on understanding the mechanisms by which homeobox genes achieve their selective functions during embryogenesis and how aberrant homeobox gene function contributes to oncogenesis. We have been pursuing these questions by unifying biochemical and developmental approaches, as well as by generating animal models. Ongoing projects revolve around two central themes: (i) roles for Msx and Dlx genes in proliferation, differentiation, and cell cycle control; and (ii) roles for Nkx3.1 in prostate development and cancer.

Roles for Msx and Dlx genes in cellular proliferation, differentiation, and cell cycle regulation

In our ongoing work we have addressed the molecular mechanisms by which Msx genes control the balance between cellular proliferation and differentiation during development. This remains a key question for understanding homeobox gene function since many such genes have been implicated as regulators of these processes yet the mechanisms by which they mediate these functions are not well understood. We have found that forced expression of Msx genes in a variety of cell culture models inhibits differentiation of mesenchymal progenitors, including muscle, bone, cartilage and fat. Furthermore, we have found that Msx genes act as general inhibitors of differentiation through up-regulation of cyclin D1, as well as CDK4 activity. This mode of regulation appears to be physiologically relevant since transgenic mice overexpressing Msx1 in the mammary epithelium display perturbed mammary gland development that is accompanied by increased expression of cyclin D1.

Notably, cyclin D1 is upregulated in a high percentage (~40%) of breast cancers yet gene amplification occurs in a significantly smaller percentage (~15%) of tumors. Thus, we are exploring the idea that upregulation of Msx may account for increased cyclin D1 expression in a subset of breast tumors. Indeed, we and others have demonstrated aberrant Msx expression in a variety of cancers. Analysis of a functional role for Msx in breast and other carcinomas, as well as additional downstream targets for Msx, represent a major focus of our current studies. Our Msx1 transgenic mice provide an excellent resource to pursue these studies, as well as to explore the role of Msx1 in mammary gland differentiation and carcinoma.

Role for Nkx3.1 in prostate development and cancer

Prostate cancer is the most commonly diagnosed neoplasm, and ranks second to lung cancer as the leading cause of cancer death in American men. However, the molecular mechanisms that lead to the initiation and progression of prostate carcinoma are poorly understood. Our studies have shown that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis, and that it is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age.

Taken together with the observation that human NKX3.1 maps to a "hotspot" for human prostate cancer, we have been testing the hypothesis that NKX3.1 maintains the differentiated state of normal prostate, while its loss represents a predisposing event for prostate carcinogenesis. Indeed, Nkx3.1 displays tumor suppressor activities in cell culture and in nude mice, and expression of NKX3.1 protein is lost or reduced in human prostate cancer. Moreover, the prostatic epithelial hyperplasia and dysplasia observed in Nkx3.1 mutant mice progresses to prostate intraepithelial neoplasia, which shares similar histological and molecular features to precursors of human prostate carcinoma. Furthermore, we have found that loss of Nkx3.1 collaborates with loss of the Pten tumor suppressor gene in prostate cancer progression. These mutant mouse models provide a framework for assembling a molecular progression pathway of human prostate cancer based on analysis of mutant mouse phenotypes.

While many homeobox genes have been implicated in carcinogenesis, Nkx3.1 is unusual in that it is a candidate tumor suppressor gene, rather than an oncogene. Although there is no evidence for mutations of the human NKX3.1 coding region in prostate tumors, our analysis of Nkx3.1 heterozygous mice demonstrates haploinsufficiency for the epithelial dysplasia phenotype. Furthermore, we have observed reduced expression and increased heterogeneity of NKX3.1 expression in human prostate cancer. Therefore, loss of a single NKX3.1 allele may be sufficient to promote prostate carcinogenesis in humans. Since candidate tumor suppressor genes are often not mutated in prostate tumor specimens, haploinsufficiency may be of general significance in prostate cancer. In summary, the Nkx3.1 mutant mice provide a unique animal model for examining the relationships between normal prostate differentiation, early stages of prostate carcinogenesis, and mechanisms of progression.

Pathway for human prostate cancer progression. Stages of progression are correlated with loss of specific chromosome regions and candidate tumor suppressor genes.

Selected Publications1