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Jeff Holt, M.D. |
My laboratory has been interested in analyzing the function of genes with
clear and important roles in cancer for the past 10 years, spanning both the
study of activated oncogenes and tumor suppressor/cancer predisposition genes.
Although our work is firmly grounded in basic science, our ultimate goal is to
translate the advances of basic cancer genetics research into clinical
practice.
We have used
genetic and biochemical analysis of human BRCA1 and BRCA2 genes to study the
role of these genes in breast, ovary, and prostate cancer. Our access to
families with hereditary breast cancer and identification of human cancer cell
lines which are hemizygous for the Ashkenazi BRCA1 and BRCA2 mutations have
allowed us to demonstrate that BRCA1 functions as a growth inhibitor and tumor
suppressor, and that both BRCA1 and BRCA2 function in DNA repair.
Published
studies of BRCA2 defective cancer cells demonstrate that BRCA2 mutant human
cancers have defective DNA repair (analagous to studies reported in knockout
mice) and are hypersensitive to ionizing radiation and certain drugs in vitro
and in vivo. These results suggest that genetic testing might be extended from
risk assessment to predicting the response to specific therapies.
My NCI-funded
R01 grant studies mechanism through which BRCA2 influences Rad51 cellular
localization and function, and how these mechanisms contribute to radiation
sensitivity and breast carcinogenesis. Robert Sclafani, Heide Ford, and Andy
Kraft and I have discussed developing a program project analyzing DNA repair and cell cycle in cancer.
In
collaboration with a number of clinical investigators, we have performed a
number of gene therapy trials of retroviral BRCA1 gene therapy for ovary
and prostate cancer. We are currently proceeding toward a breast cancer clinical
trial of BRCA1 gene therapy .
Recent Publications: (partial
from 75 publications excluding
abstracts):
Jensen, R.A., D.L. Page, and J.T. Holt. Identification of genes expressed in premalignant breast disease by microscopy-directed cloning. Proc. Natl. Acad. Sci. USA 91:9257-9261, 1994.
Thompson, M.E., R.A. Jensen, P.S. Obermiller, D.L. Page, and J.T. Holt. Decreased expression of BRCA1 accelerates growth and is frequently present during sporadic breast cancer progression. Nature Genetics 9:444-450, 1995.
Arteaga, C.L. and J.T. Holt. Tissue-targeted antisense anti-fos retroviral vector inhibits established breast cancer xenografts in nude mice. Cancer Research 567:1098-1103, 1996.
Holt JT, ME Thompson, C Szabo, C. Robinson-Benion, CL Arteaga, M-C King, and R.A. Jensen. Growth retardation and tumor inhibition by BRCA1. Nature Genetics 12:298-302, 1996.
Jensen, R.A., Thompson, M.E., Szabo, C., Jetton, T.L., R. van der Meer, Helou, B., Tronick, S.R., Page, D.L., King, M-C, Holt, J.T. BRCA1 is secreted and exhibits properties of a granin. Nature Genetics.
Jensen, R.A., Thompson, M.E., Jetton, T., van der Meer, R., Helou, B., Tronick, S.R., Page, D.L., Holt, J.T., Tronick, S.R., Gown, A.M., Ostermeyer, B., Schietz, D., Szabo, C., and King, M.-C. BRCA1 protein products. In Reply: Nature Genetics 13:269-272, 1996.
Jotte, R.M., and Holt, J.T. Myristylation of FBR v-fos dictates the differentiation pathways in malignant osteosarcoma. J. Cell Biol. 135:457-476, 1996.
Jensen, R.A., Page, D.L., Holt, J.T. RAP-PCR using RNA from tissue microdissection. In: Methods Enzymology. P. Liang and A. Pardee (eds). Humana Press Inc. 85:277-283, 1997.
Abbott, D.W. Holt, J.T. FBR vfos inhibits the cellular response to ionizing radiation in a myristylation-dependent manner. J. Biol. Chem. 272:14005-14009, 1997.
Tait, D.L., Obermiller, P., Redlin-Frazier, S., Jensen, R.A., Welcsh, P., Dann, J., King, M.-C., Johnson, D., Holt, J.T. A phase I trial of retroviral BRAC1 gene therapy in ovarian cancer. Clinical Cancer Research 3:1959-1968, 1997.
Page, D.L., Dupont, W.D., Holt, J.T., Jensen, R.A. Directions and associations I premalignant breast disease: the importance role of non-comedo ductal carcinoma in situ. Endocrine Related Cancer 4:105-112, 1997.
Holt, J.T. Breast cancer genes: clinical consideration. NY Academy of Sciences Press. NY Acad. Sci. 833-34-41, 1997.
Abbott, D.W. Holt, J.T. FBR v-fos inhibits adipogenesis and both the activity and expression of C/EBPa, a key regulator of adipocyte differentiation. J. Biol. Chem. 272:32454-32462, 1997.
Obermiller, P.S., Pilaro, A., Arteaga, C.L., Holt, J.T. Distribution and toxicity of retroviral vectors after intracavitary delivery in mouse and man. In: Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors. E. Wickstrom (ed.). Marcel Dekker, Inc. pp. 239-255, 1998.
Steiner, M.S., Anthony, C.T., Lu, Y., Holt, J.T. Antisense c-myc retroviral vector suppresses established human prostate cancer. Human Gene Therapy 9:747-755, 1998.
Tait, D.L., Jensen, R.A., Gralow, J., King M.-C., Johnson, D.H., Holt, J.T. Gene therapy for breast and overian cancer with BRCA1. Breast Disease 10:89-98, 1998.
Abbott, D.W., Freeman, M.L., Holt, J.T. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J. Natl. Canc. Inst. 90:978-985.
Abbott, D.W., Holt, J.T. MAP kinase kinase 2 (MEK2) activation is essential for progression through the G2/M checkpoint arrest in cells exposed to ionizing radiation. J. Biol. Chem. 274-2732-2742, 1999.
Abbott, D.W., Thompson, M.E., Robinson-Benion, C., Jensen, R.A., Holt, J.T. BRCA1 expression restores radiation resistance in BRCA1-defective cancer cells through enhancement of transcription coupled DNA repair. J. Biol. Chem. 274:18808-18812, 1999.
Tait, D.L., Hatmaker, A.R., Redlin-Frazier, S.,
Obermiller, P.S., Holt, J.T. Ovarian cancer BRCA1 gene therapy:
Phase I & II trial differences in immune response and vector stability.
Clin. Cancer Res. 5:1708-1714, 1999.
Tait, D.L., Obermiller, P.S., Holt, J.T. Pre-clinical studies of a new generation retroviral vector for overian cancer BRCA1 gene therapy. Gyn. Oncol. 79:471-476, 2000.
