Director, Cancer Chemoprevention
Department of Cancer Prevention and Population Sciences
Chair, Cancer Pathology and Prevention Program
Roswell Park Graduate Division of the University at Buffalo (UB)
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo New York USA 14263
Tel: 716-845-8875
Fax: 716-845-8100
E-mail: clement.ip@roswellpark.org

Dr. Clement Ip joined the faculty at Roswell Park Cancer Institute (RPCI) in 1975 as Cancer Research Scientist I in the Department of Breast Surgery. He was appointed Distinguished Member in the Department of Cancer Prevention and Population Sciences in 2002. He also serves as Chair of the Cancer Pathology and Prevention Program of the Roswell Park Graduate Division of the University at Buffalo (UB).

Dr. Ip earned his doctoral degree in Nutritional Biochemistry at the University of Wisconsin, Madison, in 1973. He then completed postdoctoral training in Endocrinology at the Upstate Medical Center, Syracuse, NY in 1975. He has held numerous positions at RPCI in the Departments of Breast Surgery and Experimental Pathology including Cancer Research Scientist II (1977-1984); Cancer Research Scientist IV (1984-1991) and Associate Member (1991-2002).

Dr. Ip's research interests focus on biology and biochemistry of breast cancer, nutritional modification of mammary carcinogenesis and cancer chemoprevention. His two primary areas of chemoprevention research focus on conjugated linoleic acid and selenium.

Dr. Ip is a member of The American Association for Cancer Research, American Society for Nutritional Sciences and the International Association for Breast Cancer Research.

Dr. Ip has authored or co-authored more than 185 journal publications, book chapters and abstracts. He frequently serves as an ad hoc reviewer for Cancer Research, Carcinogenesis, Cancer Letters, International Journal of Cancer, Journal of National Cancer Institute, Journal of Nutrition, American Journal of Clinical Nutrition, Biological Trace Element Research, Anticancer Research and Nutrition and Cancer.

Current Program
Chemoprevention of Breast Cancer
A. Selenium Chemoprevention of Cancer.
Selenium supplementation has been reported to suppress carcinogenesis in many animal models. The cancer protective effect of selenium in humans is also supported by epidemiological data as well as by intervention trials. With the use of different approaches, we have obtained strong evidence which suggests that selenium has to be metabolized in order to express its anticancer activity. Current research is focused on the following areas:

Tissue speciation of selenium metabolites by using state-of-the-art technique of HPLC- ICP-MS, these metabolites include methylated selenol, diselenide, selenylsulfide, as well as the identification of possible oxidized methylated selenium species. This type of analysis has never been attempted before in selenium biochemistry research.

Studies of target protein activation or inactivation through intramolecular disulfide bond formation by monomethylated selenium species. We will initially concentrate on thioredoxin reductase and protein kinase C.

Development of stable precursor to deliver selenium metabolite with high anticancer efficacy and low toxicity. A collaborative network is presently in place to implement this process which involves chemical synthesis of new compounds, in vitro screening through a defined panel of biological and molecular assays, and in vivo testing of toxicity, pharmacology, and chemopreventive activities.

The biology of selenium-mediated suppression of clonal expansion of preneoplastic lesions in the mammary gland.

Molecular mechanism of selenium effect on cell cycle regulatory proteins and cell death regulatory proteins.

Characterization of biomarkers specific for inhibition of proliferation and induction of apoptosis by selenium intervention.

Identification of new genes modulated by selenium intervention and associated follow-up studies to evaluate biological significance.

B. Mammary Cancer Prevention by Conjugated Linoleic Acid.
Conjugated linoleic acid (CLA) is a term which refers to a collection of positional isomers of octadecadienoic acid with conjugated double bonds. Contrary to linoleic acid which is known to stimulate carcinogenesis, CLA at 1% in the diet produces protective effect. CLA is a natural food constituent. Milk and dairy products are good sources of CLA because of the unique metabolic capability of rumen bacteria in converting linoleic acid to CLA. Recent research has demonstrated that the CLA content in milk can be increased 10-fold or more by feeding cows a fat supplement high in linoleic acid. Thus “anticancer designer food” is more than just a concept in the repertoire of new strategy for cancer prevention.

We have described two distinct activities of CLA in mammary cancer prevention. First, CLA feeding limited to the period of pubescent mammary gland development is sufficient to confer a lasting protection against the subsequent induction of mammary tumors. This effect is probably due to a decrease in mammary epithelial branching and proliferation of terminal end bud cells which are the target sites of mammary carcinogenesis.

Second, CLA is also capable of suppressing neoplastic progression. The inhibitory response is dose-dependent and requires a continuous availability of CLA. Additionally, our in vitro experiments show that CLA decreases cell growth and induces apoptosis in a primary mammary epithelial cell culture system. Future research will test the hypothesis that CLA suppresses mammary gland preneoplastic lesions by blocking cell proliferation and/or by stimulating apoptosis. Detailed mechanistic studies will be carried out first in cell culture, followed by animal experiments to validate the relevance of the in vitro information.

Current research is focused on the following areas

• Inhibition by CLA of mammary stromal cell differentiation to endothelial cells.
• Studies of CLA effect on mammary stromal-epithelial interactions in a co-culture model.
• Suppression of tumor progression in vivo by CLA via an impairment of angiogenesis.
• An elucidation of the relationship between CLA isomer specificity and biological activity.
• Characterization of specific step(s) in the MAP kinase signal transduction pathway as affected by CLA.
• Molecular mechanism by which CLA stimulates apoptosis in mammary epithelial cells.
• CLA feeding on the expression of proliferative and apoptotic markers in defined target cell populations of the mammary gland. These studies are designed to apply the in vitro information of Aims 5 and 6 to the in vivo model to validate the use of molecular surrogate endpoints in future CLA intervention trial.
• An investigation of how CLA might affect the pace and outcome of mammary gland development and to elucidate the biological significance in relation to modulation of cancer risk. The animal experiments are designed to address whether CLA nutrition during pubescence may have a durable suppressive effect on maturation of the mammary epithelium and therefore resulting in a lower cancer risk later on in life.
• Molecular mechanism of CLA effect via PPAR (alpha, beta and gamma) activation and modulation of PPAR-response genes. Present focus is on adipocyte-type fatty acid binding protein which is functionally related to mammary derived growth inhibitor.
• Metabolism of CLA by elongation and desaturation and the impact on the endogenous biosynthesis of eicosanoids.
• Direct effect of CLA and CLA metabolites on cyclooxygenase and lipoxygenase enzymes.
• The development of CLA-enriched designer foods through collaboration with dairy science. The project involves in vivo testing of using food to deliver specific isomeric form of CLA for cancer prevention.

Key Publications

Ip, M.M., Masso-Welch, P.A., and Ip, C. Prevention of mammary cancer with conjugated linoleic acid: Role of the stroma and the epithelium. J. Mammary Gland Biol. Neoplasia 8: 101-116, 2003.

Dong, Y., Lee, S.O., Zhang, H., Marshall, J., Gao, A.C., and Ip, C. Prostate specific antigen expression is down-regulated by selenium through disruption of androgen receptor signaling. Cancer Res., 64: 19-22, 2004.

Masso-Welch, P.A., Zangani, D., Ip, C., Vaughan, M.M., Shoemaker, S.F., McGee, S.O., and Ip, M.M. Isomers of conjugated linoleic acid differ in their effects on angiogenesis and survival of mouse mammary adipose vasculature. J. Nutr. 134: 299-307, 2004.

Park, E.-M., Choi, K.-S., Park, S.-Y., Kong, E.-S., Zu, K., Wu, Y., Zhang, H., Ip, C., and Park, Y.-M. A display thiol-proteomics approach to characterize global redox modification of proteins by selenium: Implications for the anticancer action of selenium. Cancer Genomics & Proteomics 2: 25-36, 2005.

Zhang, H., Dong, Y., Zhao, H., Brooks, J.D., Hawthorn, L., Nowak, N., Marshall, J.R., Gao, A.C., and Ip, C. Microarray data mining for potential selenium targets in chemoprevention of prostate cancer. Cancer Genomics & Proteomics 2: 97-114, 2005.

Wu, Y., Zhang, H., Dong, Y., Park, Y., and Ip, C. Endoplasmic reticulum (ER) stress signal mediators are targets of selenium action. Cancer Res. 65: 9073-9079, 2005.

Dong, Y., Zhang, H., Gao, A.C., Marshall, J.R., and Ip, C. Androgen receptor signaling intensity is a key factor in determining the sensitivity of prostate cancer cells to selenium inhibition of growth and cancer specific biomarkers. Mol. Cancer Ther. 4: 1047-1055, 2005.

Zu, K., Bihani, T., Lin. A., Park, Y.-M., Mori, K., and Ip, C. Enhanced selenium effect on growth arrest by BiP/GRP78 knockdown in p53-null human prostate cancer cells. Oncogene 25: 546-554, 2006.

Wu, Y., Zu, K., Warren, M.A., Wallace, P.K., and Ip. C. Delineating the mechanism by which selenium deactivates Akt in prostate cancer cells. Mol. Cancer Ther. 5:246-252, 2006.

Ou, L., Ip, C., Lisafeld, B., and Ip, M.M. Conjugated linoleic acid induces apoptosis of murine mammary tumor cells via Bcl-2 loss. Biochem. Biophys. Res. Commun. 356: 1044-1049, 2007.

Li, S., Zhou, Y., Dong, Y., and Ip, C. Doxorubicin and selenium cooperatively induce Fas signaling in the absence of Fas/Fas lgand interaction. Anticancer Res. 27: 3075-3082, 2007.