Martin Tenniswood       Professor, Coleman Foundation Chair Ph.D., Queen's, 1979

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Prostate and Breast Cancer - Apoptosis

The overall theme of the laboratory is the study of apoptosis in prostate, breast and endometrial cancer. The goal of this research is to improve current hormone therapies for these diseases and to obtain a better understanding of the development of hormone refractory disease, which ultimately leads to the death of the patient. Our approach has been to clone, and characterize the expression of a number of apoptosis related genes that are involved in prostate and mammary gland regression.
Many of genes that we have cloned influence, or are regulated by, the extracellular matrix (ECM) and modulate the interactions between the stroma and epithelium that are required for epithelial homeostasis. The co-ordinate induction of these genes after hormone ablation appears to be a critical step the apoptotic pathway in glandular epithelial cells, and leads to the disruption of the interaction between the dying cell and its underlying ECM. There is considerable evidence indicating that apoptosis occurs in several stages, and that the essential genes are induced de novo (or recruited from other cellular functions) prior to the onset of DNA fragmentation, which requires the activation of pre-existing endonucleases and nuclear proteases. We have been struck by the remarkably biochemical similarity between the processes of cell death and metastasis, since degradation of the extracellular matrix is a prerequisite for both processes. This has led us to hypothesize that tumor cells may acquire an invasive phenotype if DNA fragmentation is abrogated during apoptosis. We are examining this hypothesis in orthotopic and transgenic mouse model systems.

 

The Role of Histone Deacetylases in Cell Death in Prostate Cancer

(Somdutta Roy, Mike Abraham, Nicholas Russell, Randy Jeffrey)

Standard treatments for early stage localized prostate disease are either surgery or radiation therapy. For locally invasive and metastatic disease, these therapeutic options are often not applicable, and current therapies focus principally on androgen ablation using anti-androgens. This treatment usually induces remission. However, in the majority of cases, the tumor subsequently re-emerges in a hormone refractory form for which there is no good curative option. The limited therapeutic options for locally invasive and metastatic disease, and the poor prognosis once the tumor has spread beyond the prostatic capsule has lead to the search for new treatments. A new class of anticancer agents called Histone Deacetylase Inhibitors (HDIs), have shown promise in vitro for the treatment of leukemia, neuroblastoma, breast, and colon cancer. The ability of HDIs such as suberoylanilide hydroxamic acid (SAHA), phenylbutyrate and Trichostatin A (TSA) , is thought to be due to their ability to inhibit the deacetylation of histones by histone de-acetylases (HDACs). This leads to the accumulation of acetylated histones, which is thought to facilitate the re-expression of genes, such as the cell cycle inhibitors p21WAF1/CIP1 and p27KIP-1, which are often silenced during cancer progression. Thus HDIs may represent a new class of drugs for the treatment of cancer, specially the more aggressive and metastatic form of cancer. We have explored the mechanism of action of a new HDI called CG-1521, a hydroxamic acid related to SAHA, which has a remarkable safety profile in phase 1 clinical trials for leukemia.

We have recently shown that in addition to changes in the acetylation of histones H3 and H4, TSA and CG-1521 induce apoptosis very effectively in both androgen receptor positive (AR+) non-metastatic prostate cancer cells and androgen receptor negative (AR-) metastatic tumor cells. These HDIs induce cell cycle arrest and apoptosis by different mechanisms. CG-1521 stabilizes acetylated p53 which induces p21 transcription and subsequent cell cycle arrest and bax transcription, translocation, cleavage and insertion into the mitochondrial membrane which induces cytochrome c release and apoptosis. This is accompanied by the inhibition of HDAC1 and the loss of HDAC2. TSA stabilizes acetylated p53, induces p21 transcription leading to cell cycle arrest but does not induce bax transcription, translocation or cleavage. TSA only inhibits the activity of HDAC 1, and has no discernible effect on the levels of HDAC 2. These studies represent the first analysis of the mechanism of action of HDIs in prostate cancer, and are the first to demonstrate that HDIs probably exert the majority of their effects through regulation of the acetylation of p53, and transactivation of the p21 promoter activity of and not simply through changes in chromatin conformation.

Role of Vitamin D in Prostate Cancer Progression

(Sarah Mordan-McCombs, Randy Jeffrey)

Epidemiological, molecular and cellular studies have implicated vitamin D3, a fat soluble vitamin, in the development and/or progression of human prostate cancer. The biologically active form of vitamin D3 is 1,25 dihydroxyvitamin D3 (1,25D), a steroid which induces growth arrest and apoptosis in a wide variety of normal and transformed cells, including those derived from prostate. The activation of vitamin D3 to 1,25D in the body is intricately linked to dietary calcium, another nutrient which has been associated with prostate cancer risk in epidemiological studies. Our studies utilize genetically engineered mice and orthotopic xenograft model systems to address the interactions between vitamin D and calcium in regulation of prostate growth and tumorigenesis. Our overall hypothesis is that the vitamin D receptor represents a nutritionally modulated growth regulatory gene in prostate.
To determine whether alterations in dietary calcium or VDR signaling can prevent prostate tumorigenesis in a transgenic mouse model we have crossed LPB-Tag transgenic mice, which predictably develop prostate cancer, with VDR knockout (VDRKO) mice to generate transgenic mice with and without VDR. We are currently analyzing the histology and time to progression in VDRKO and WT transgenic mice to determination of the influence of VDR ablation on prostate tumorigenesis, and to assess the impact of dietary calcium on prostate tumor development.
We are also assessing the impact of dietary calcium and a vitamin D analog on progression of early stage human prostate cancer. In this aim we will utilize an androgen responsive human prostate cancer cell line (PC346C) orthotopically injected into testosterone-supplemented immunodeficient mice to determine whether manipulation of dietary calcium or treatment with a vitamin D analog affects growth, progression or hormonal sensitivity of early stage human prostate tumors. These studies will establish the impact of dietary calcium and the vitamin D analog EB1089 on growth and progression of human prostate cancer and prostate tumor sensitivity to the anti-androgen Casodex

Interaction between Dietary and Natural Products with Conventional Therapy for Prostate and Breast Cancer

(Tsuyuki Nishino, Peter McHenry, and Winnie Wang)

Over the last ten years Prostate Specific Antigen (PSA) based screening and heightened awareness has lead to a substantial increase in the number of men diagnosed with early stage, localized prostate cancer. Treatment of localized prostate cancer can be broadly divided into four categories: surgery, hormone therapy, radiation therapy or watchful waiting. With the recent success of the Bicalutamide 150mg (Casodex) Early Prostate Cancer (EPC) Programme, many physicians are now encouraging their patients to add Casodex to other standard therapies. These same patients are being exposed to information in the lay literature regarding the benefits of dietary components (particularly green tea, soy products and cooked tomato products) as well as herbal extracts such as saw palmetto and PC-SPES. While epidemiological, and molecular and cellular studies have shown that some of these dietary components are associated with lower incidence of prostate cancer, there have been no studies that have examined the effects of these components on prostate cancer progression. Furthermore, the possible (adverse) effects of these dietary components on standard therapies, particularly hormone therapy, have not been examined. We are using the PC-346C orthotopic model of prostate cancer to examine the interactions between green tea consumption and hormone therapy in regulation of prostate tumor progression and metastasis. These experiments will serve as a paradigm for the study of the interactions of other nutrients, herbal extracts or natural products with standard therapy. These studies have the potential to impact on dietary recommendations for men diagnosed with early stage prostate cancer who contemplate standard therapies.  We have recently extended these studies to examine the mechanism of action of Iejimalide B, a marine macrolide extracted from sea slugs, in prostate cancer cells.

SELECTED PUBLICATIONS (2001-2007)

1. Morrissey C., Lakins, J. N., Moquin, A., Tenniswood, M and Hussain, M (2001) A Antigen Capture Assay for the Measurement of Serum Clusterin Concentrations. Journal of Biochemical and Biophysical Methods 48: 13-21.

2. Suh E., Wang Z. Swain G.P., Tenniswood, M., and Traber, P.G. (2001) Clusterin Gene Transcription Is Activated By Caudal-Related Homeobox Genes In The Intestinal Epithelium. American Journal of Physiology 280: G149-G156.

3. Wong, P. Ulyanova, T., Organisciak D.T., Bennett, S.A.L., Lakins, J., Arnold, J, Kutty, R.K., Tenniswood, M., vanVeen, T., Darrow R.M., and Chader, G. (2001) Expression of Multiple Forms of Clusterin During Light-Induced Retinal Degeneration. Current Eye Research 23:157-165.

4. Lakins, J.N., Poon, S., Easterbrook-Smith S., Carver J.A., Tenniswood, M. and Wilson M.R. (2002) Evidence that Clusterin Has Discrete Chaperone and Ligand Bind Sites. Biochemistry 41:282-291.

5. Morrissey, C., Buser, A., Scolaro, J., O’Sullivan, J., Moquin, A., and Tenniswood, M. (2002) Changes in the Hormonal Sensitivity in the Ventral Prostate of Aging Sprague-Dawley Rats. Journal of Andrology 22: 341-351.

6. Zhan P., Lee, E.C.Y., Packman, K. and Tenniswood, M. (2003) Induction of Invasive Phenotype by Casodex in hormone sensitive Prostate Cancer Cells. Journal of Steroid Biochemistry and Molecular Biology 83: 101-111.

7. Lee, E.C.Y., Zhan, P., Packman, K., and Tenniswood, M. (2003) Anti-androgen induced cell death in LNCaP Human Prostate Cancer Cells. Cell Death and Differentiation 10:761-771.

8. Flanagan, L., Packman, K., Juba, B*., O’Neill, S., Tenniswood, M. and Welsh, J. (2003) Efficacy of Vitamin D compounds to modulate Estrogen Receptor Negative Breast Cancer Growth and Invasion. Journal of Steroid Biochemistry and Molecular Biology 84: 181-192.

9. O’Sullivan, J., Whyte, L., Drake, J., and Tenniswood M. (2003) Alterations in the Post-translational Modification and Intracellular Trafficking of Clusterin in MCF-7 Cells During Apoptosis. Cell Death and Differentiation 10: 914-927.

10. Iyengar, P., Combs, T.P., Shah, S.J., Gouon-Evans, V., Pollard, J.W., Albanese, C., Flanagan, L., Tenniswood, M.P., Guha, C., Lisanti, M.P., Pestell, R. and P. E. Scherer (2003) Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene, 22:6408-6423.

11. Tang, H., Brown, M., Ye, Y., Huang, G., Zhang, Y., Wang, Y., Zhai, H., Chen, X., Shen, T.Y., Tenniswood, M. (2003) Prostate targeting ligands based on N-acetylated -linked acidic dipeptidase. Biochemical and Biophysical Research Communications 307: 8-14.

12. Oliver, A.J., Wiest, O., Helquist, P., Miller, M. and Tenniswood M. (2003) Conformational and SAR analysis of NAALADase and PSMA inhibitors Bioorganic and Medicinal Chemistry 11(20): 4455-4461.

13. Lee, E.C.Y. and Tenniswood, M. (2004) Programmed Cell Death and Survival Pathways in Prostate Cancer Cells. Archives of Andrology 50:27-32. (note that the pdf has a different title and is longer. Prior to publication, the journal asked us for a short, edited version for the print version of the manuscript).

14. Lee, E.C.Y. and Tenniswood, M. (2004) Emergence of Metastatic Hormone Refractory Disease in Prostate Cancer after Anti-androgen Therapy. Journal of Cellular Biochemistry 91:27-32.

15. Chrenek, M.., Erickson T., Gee, C. Lee E.C.Y., Gilmore K..,Tenniswood, M. and Wong, P. (2004) Comparative Functional Genomics: Analysis of Changes in mRNA Profiles in Multiple Model Systems for Understanding Basic Biological Phenomenon. Transactions of Integrated Biomedical Informatics and Enabling Technologies 1:43-54. (epub)

16. Tenniswood, M. and Lee, E.C.Y. (2004) On the Trail of Cell Death Pathways in Prostate Cancer. Cancer Biol. Therapeutics. 3:779-771.

17. Zierau O., O'Sullivan, J., Morrissey, C., McDonald D., Wünsche W., Schneider,M. R. Tenniswood, M. and Vollmer, G. (2004) Tamoxifen exerts agonistic effects on clusterin and complement C3 gene expression in RUCA-I primary xenografts and metastases but not normal uterus. Endocrine Related Cancer 11: 823-830.

18. Roy S., Packman K., Jeffrey, R. and Tenniswood M. (2005) Inhibition of Histone Deacetylases Stabilizes Acetylated p53 and Induces Cell Cycle Arrest and Apoptosis in Prostate Cancer Cells. Cell Death and Differentiation 12: 12: 482-491.

19. Mordan-McComb S., Brown T. Welsh J. and Tenniswood M. (2007) Dietary Calcium Does Not Affect Prostate Tumor Progression in LPB-Tag Transgenic Mice. Journal of Steroid Biochemistry and Molecular Biology. 103:747-51

20. Roy S., and Tenniswood M. (2007) Site Specific Acetylation of p53 Directs Selective Transcription Complex Assembly Journal of Biological Chemistry 282: 4765-4771.

21. Suckow, M., Rosen, E., Wolter, W.R., Sailes, V., Jeffrey R., and Tenniswood, M. (2007) Prevention of human PC-346C prostate cancer growth in mice by xenogeneic tissue vaccine. Cancer Immunology and Immunotherapeutics 58:1275-1283.

22. Morrissey, C., Brown, M., O’Sullivan J., Weathered, N., Watson, R., and Tenniswood, M. (2007) Epigallocatechin-3-Gallate and Bicalutamide Cause Growth Arrest and Apoptosis in NRP-152 and NRP-154 Prostate Epithelial Cells. International Journal of Urology in press.

23. Mordan-McCombs, S., Valrance, M., Zinser, G.M., Tenniswood, M. and Welsh, J.E. (2007) Calcium, vitamin D and the Vitamin D receptor: impact on prostate and breast cancer in preclinical models. Nutrition Reviews, in press

 

 

CURRENT LAB PERSONNEL

Graduate Students:

 

Randy Jeffrey, B.Sc., Queen’s University, Kingston ON, Canada (2003)

Sarah Mordan-McCombs, BS, DePauw University, Greencastle, IN (2003)

Peter McHenry, BS, Union College, Lincoln, Nebraska (2004)

Nicholas Russell, BS, St. Francis University, Fort Wayne, IN (2005)

 

Technician:

Ken Jones

Recent Alumni Laboratory Members:

Colm Morrissey Ph.D. (University College Dublin, 1999) Post-Doctoral Fellow, Department of Urology, University of Washington, Seattle WA

Jacintha O'Sullivan, Ph.D. (University College Dublin, 2000) Post-doctoral Fellow, Conway Institute for Bioscience Dublin Ireland

Zhengqi Wang, Ph.D. (University of Notre Dame, 2000) Research Assistant Professor, Case Western Reserve University, Cleveland OH.

Dana McDonald, M.S. (University of Notre Dame, 2001) Technician, Indiana University Medical School, Indianapolis, IN

Kathryn Packman, PhD. (University of Notre Dame, 2000) Principle Scientist and Acting Head, In vivo Biology, Hoffman-Roche, Nutley NJ)

Kerry Gilmore PhD. (University of Wollongong, 1999) Associate Lecturer, University of Wollongong, NSW, Australia)

Ping Zhan , PhD. (University of Notre Dame, 2003) Bio-statistician, Celera Inc, San Francisco, CA

Yao Wang, M.S. (University of Notre Dame, 2003) Technician, Department of Computer Science, New Jersey Technical Institute.

Edmund Lee PhD, (University of Notre Dame (2004) Post-Doctoral Fellow Fred Hutchinson Cancer Research Center, Seattle WA.

Lorna Whyte, Ph.D., University of Notre Dame (2005)Post-Doctoral Fellow, Illinois Institute of Technology Research Institute (IITRI) Chicago, IL.

Somdutta Roy, Ph.D., University of Notre Dame (2006) Post-Doctoral Fellow, University of California, San Francisco.