Richard J. Santen

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University of Virginia
School of Medicine
Internal Medicine
Professor of Medicine/Assoc. Dir. (Clin. Res., Cancer Center)Appointed: 1979/1995

Mailing Address

#513 Jordan Annex
University of Virginia
Charlottesville, Virginia 22908
United States

Contact Information

Phone: (804) 924-2961
Fax: (804) 982-4186
rjs5y@virginia.edu
http://www.med.virginia.edu

Qualifications

M.D., University of Michigan, Medicine, 1965.
A.B., Holy Cross College, 1961.

Expertise and Research Interests

This research program is directed toward an understanding of the cellular and molecular mechanisms responsible for the ability of breast cancer cells to continue to grow in the presence of very low circulating levels of estradiol in post menopausal women. Clinical observations indicate that women with hormone dependent breast cancer respond sequentially to secondary or tertiary hormonal therapies aimed at depriving them of an estrogenic stimulus. We have raised the hypothesis that e stradiol deprivation causes an adaptive hypersensitivity to estrogen. Two mechanisms are being actively explored. One is that cells reversibly develop molecular alterations which enhance their level of sensitivity to estradiol. The other is that precursors of estradiol may beconverted into estrogen in breast tumor tissue and that an adaptive enhancement of this process allows cells to synthesize greater quantities of estrogen.Evidence for the concept of enhanced sensitivity to estradiol has been obtained in breast cancer cells grown in culture and deprived of usual levels of estrogen. Under these conditions, cells shift their level of sensitivity to estradiol by a four log difference in concentration. Further, upon re-exposure to estrogen, the cells adapt with a diminished sensitivity to estradiol. The working hypothesis is that transcription intermediary factors are increased in long term estradiol deprived cells and that this effect results in enhancements of sensitivity. Recent data from other laboratories suggest that receptor mediated transcription represents an on/off switch mechanism whereas the transcription intermediary factors act as rheostats to modulate the actualrate of transcription. These coactivator factors have been recently cloned. Co-repressors have also been desribed which act along with coactivators as a bivalent system to enhance or dampen hormone stimulated transcription. It is postulated that an increase in co-repressor might be responsible for the remarkable shifts in dose response to estradiol observed.Ongoing studies are addressing the molecular mechanisms responsible for enhanced sensitivity. Experiments are designed to evaluate the level of co-activators and co-repressors as well as the rate of phosphorylation of estrogen receptors, the specific genes stimulated by estrogens which control the level of cellular proliferation, and the interactions of growth factors with altered responsiveness to estrogens.The practical significance of these studies is that more potent inhibitors of estradiol biosynthesis or action will be required to overcome the enhanced sensitivity to levels of estradiol present in tissues. To this end, we have been developing third generation inhibitors of aromatase, the rate limiting step in estradiol biosynthesis, as therapy of patients with relapse following initial reduction of estradiol levels induced by oophorectomy. A corollary of our hypothesis is that cells will become hypersensitive to the estrogenic effects of tamoxifen during treatment. If this is the case withdrawl of tamoxifen and substitution of potent aromatase inhibitors will be beneficial. We have demonstrated that Letrozola is nearly 10,000 fold more potent that first generation aromatase inhibitors and is capable of marked inhibitions of estradiol biosynthesis in appropriate patients.The second hypothesis is that breast cancer cells, when deprived of estradiol, will develop the ability to synthesize estradiol in situ in tumors. Using an immunohistochemical method we demonstrated that the stromal cell component of breast tumors contains the aromatase enzyme and that known enhancers of transcription can markedly stimulate the amount of aromatase present in cultured stromal cells. Dexamethasone as well as phorbol esters and cAMP acting in concert can stimulate aromatase activity by 10,000 fold. This action of fibroblasts would cause surrounding epithelial cells to secrete growth factors which in turn would stimulate proliferation of surrounding cells. We are currently addressing which specific enhancers of transcription are responsible for aromatase overexpression in breast cancer cells.The focus on overexpression of aromatase in estromal cells has led us to examine data from a wide array of experiments that suggest that aromatase overexpression may also cause breast cancer. Acting either through epigenetic of genotoxic mechanisms, estrogen may cause a stochastic array of mutations which ultimately result in a heterogeneous population of breast cancer cells. A recent grant proposal outlines a series of experiments to test the local estrogen level/carcinogenesis hypothesis. If correct, this hypothesis suggests that use of aromatase inhibitors in highly susceptible women will serve as a means of preventing breast cancer.

Other Expertise

Academic Experience:Honorary Societies: Alpha Omega Alpha, Phi Kappa PhiAcademic Awards: 1978-79, Fogarty Senior International Fellowship Award; 1992, Ciba-Geigy ANT International A ward, Eubiosia Prize; 1993, Susan G. Komen Foundation Brinker Award for Breast Cancer Research.Scientific Societies: American Clinical and Climatological Association, Association of Professors of Medicine.Editorial Boards: 1979-82, Journal of Clinical Endocrinology and Metabolism; 1980-present, Breast Cancer Research and Treatment

Keywords

COS Keywords:

Breast Cancer, Cancer Or Carcinogenesis, Endocrine System, Reproduction.

Additional Terms:

Aromatase, Autocrine, Breast, Cancer, Endocrine, Estrogen, Estrogen Hypersensitivity, In Situ Estrogen Production, Male Reproduction, Paracrine, Prevention, Receptor.

Languages

(Reading, Writing, Speaking)

French: (Fluent, Basic, Functional)

Memberships

American Clinical and Climatological Association
American College of Physicians
American Federation for Medical Research
American Society for Clinical Investigation
American Society of Andrology
American Society of Breast Disease (ASBD)
American Society of Clinical Oncology
Central Society for Clinical Research
Endocrine Society
Society for the Study of Reproduction
The Virginia Endocrine Society

Previous Positions

1994-1995, Meyer L. Prentis Cancer Center, Interim Director
1993-1995, Department of Medicine, Wayne State University, Professor and Chairman
1992-1993, Department of Medicine, Hershey Medical Center, Vice-Chairman
1986-1993, Hershey Medical Center, Pennsylvania State University, Evan Pugh Professor of Medicine
1985-1986, Hospital Necker, Paris, Visiting Professor
1966-1967, Medicine, New York Cornell, Assistant Residency
1965-1966, Medicine, New York Hospital, Cornell, Internship

Funding Received

  • Determinants of Tissue Estradiol Sensitivity, National Institutes of Health (NIH), $120,632 1st yr., 8/7/94-7/31/97
  • Mitotic Modifiers of Hormone-Dependent Breast Cancer, National Institutes of Health (NIH), $201,682 2nd year, 8/1/93-7/31/96
  • Cancer Center Support Grant, National Institutes of Health (NIH), $800,992, 4/1/92-3/31/97
  • Studies of the Ethnic Differences in 5-alpha-Reductase Activity, World Health Organization, $19,312, 6/1/91-3/31/92
  • Mitotic Modifiers of Hormone-Dependent Cancers, National Institutes of Health (NIH), $8,018,328, 7/1/88-6/30/93

Publications

  • Pauley RJ, Santner SJ, Tait LR, Bright RK, Santen RJ, Regulated CYP19 aromatase transcription in breast stromal fibroblasts., Journal of Clinical Endocrinology and Metabolism, 85(2), 837-46, 2000 Abstract
  • Shim WS, Conaway M, Masamura S, Yue W, Wang JP, Kmar R, Santen RJ, Estradiol hypersensitivity and mitogen-activated protein kinase expression in long-term estrogen deprived human breast cancer cells in vivo., Endocrinology, 141(1), 396-405, 2000 Abstract
  • Santen RJ, Petroni GR, Relative versus attributable risk of breast cancer from estrogen replacement therapy., Journal of Clinical Endocrinology and Metabolism, 84(6), 1875-81, June 1999 Abstract
  • Yue W, Santen RJ, Wang JP, Hamilton CJ, Demers LM, Aromatase within the breast., Endocrine Related Cancer, 6(2), 157-64, 1999 Abstract
  • Santen RJ, Yue W, Naftolin F, Mor G, Berstein L, The potential of aromatase inhibitors in breast cancer prevention., Endocrine Related Cancer, 6(2), 235-43, 1999 Abstract
  • Santen RJ, Harvey HA, Use of aromatase inhibitors in breast carcinoma., Endocrine Related Cancer, 6(1), 75-92, 1999 Abstract
  • Shim WS, DiRenzo J, DeCaprio JA, Santen RJ, Brown M, Jeng MH, Segregation of steroid receptor coactivator-1 from steroid receptors in mammary epithelium., Proceedings of the National Academy of Sciences (USA), 96(1), 208-13, 5 Jan 1999 Abstract
  • Jeng M H, Shupnik M A, Bender T P, Westin E H, Bandyopadhyay D, Kumar R, Masamura S, Santen R J, Estrogen receptor expression and function in long-term estrogen-deprived human breast cancer cells., Endocrinology, 139(10), 4164-74, October 1998 Abstract
  • Santner S J, Albertson B, Zhang G Y, Zhang G H, Santulli M, Wang C, Demers L M, Shackleton C, Santen R J, Comparative rates of androgen production and metabolism in Caucasian and Chinese subjects., Journal of Clinical Endocrinology and Metabolism, 83(6), 2104-9, June 1998 Abstract
  • Sinha S, Kaseta J, Santner S J, Demers L M, Bremmer W J, Santen R J, Effect of CGS 20267 on ovarian aromatase and gonadotropin levels in the rat., Breast Cancer Research and Treatment, 48(1), 45-51, March 1998 Abstract
  • Yue W, Wang J P, Hamilton C J, Demers L M, Santen R J, In situ aromatization enhances breast tumor estradiol levels and cellular proliferation., Cancer Research, 58(5), 927-32, 1 Mar 1998 Abstract
  • Yue W, Santner SJ, Masamura S, Wang JP, Demers LM, Hamilton C, Santen RJ, Determinants of tissue estradiol levels and biologic responsiveness in breast tumors., Breast Cancer Research and Treatment, 49 Suppl 1, S1-7; discussion S33, 1998 Abstract
  • Santen RJ, Martel J, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R, Pauley R, Santner S, Demonstration of aromatase activity and its regulation in breast tumor and benign breast fibroblasts., Breast Cancer Research and Treatment, 49 Suppl 1, S93-9; discussion S1, 1998 Abstract
  • Santen R J, Santner S J, Pauley R J, Tait L, Kaseta J, Demers L M, Hamilton C, Yue W, Wang J P, Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible?, Journal of Steroid Biochemistry and Molecular Biology, 61(3-6), 267-71, April 1997 Abstract
  • Masamura S, Santner S J, Gimotty P, George J, Santen R J, Mechanism for maintenance of high breast tumor estradiol concentrations in the absence of ovarian function: role of very high affinity tissue uptake., Breast Cancer Research and Treatment, 42(3), 215-26, February 1997 Abstract
  • Santner S J, Pauley R J, Tait L, Kaseta J, Santen R J, Aromatase activity and expression in breast cancer and benign breast tissue stromal cells., Journal of Clinical Endocrinology and Metabolism, 82(1), 200-8, January 1997 Abstract
  • Yue W, Santen R J, Aromatase inhibitors: rationale for use following antiestrogen therapy., Seminars In Oncology, 23(4 Suppl 9), 21-7, August 1996 Abstract
  • Masamura S, Santner S J, Santen R J, Evidence of in situ estrogen synthesis in nitrosomethylurea-induced rat mammary tumors via the enzyme estrone sulfatase., Journal of Steroid Biochemistry and Molecular Biology, 58(4), 425-9, July 1996 Abstract
  • Santen R J, Long-term tamoxifen therapy: can an antagonist become an agonist? [editorial], Journal of Clinical Endocrinology and Metabolism, 81(6), 2027-9, June 1996 Abstract
  • Berstein L M, Santen R J, Santner S J, Three-component model of oestrogen formation and regulation of intratumoural oestrogen pool in breast neoplasms., Medical Hypotheses, 45(6), 588-90, December 1995 Abstract
  • Masamura S, Santner S J, Heitjan D F, Santen R J, Estrogen deprivation causes estradiol hypersensitivity in human breast cancer cells., Journal of Clinical Endocrinology and Metabolism, 80(10), 2918-25, October 1995 Abstract
  • Klein K O, Demers L M, Santner S J, Baron J, Cutler G B Jr, Santen R J, Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole., Journal of Clinical Endocrinology and Metabolism, 80(9), 2658-60, September 1995 Abstract
  • Lipton A, Demers L M, Harvey H A, Kambic K B, Grossberg H, Brady C, Adlercruetz H, Trunet P F, Santen R J, Letrozole (CGS 20267). A phase I study of a new potent oral aromatase inhibitor of breast cancer., Cancer, 75(8), 2132-8, 15 Apr 1995 Abstract
  • Masamura S, Adlercreutz H, Harvey H, Lipton A, Demers L M, Santen R J, Santner S J, Aromatase inhibitor development for treatment of breast cancer., Breast Cancer Research and Treatment, 33(1), 19-26, 1995 Abstract
  • Santen R J, Martel J, Hoagland M, Naftolin F, Roa L, Harada N, Hafer L, Zaino R, Santner S J, Stromal spindle cells contain aromatase in human breast tumors., Journal of Clinical Endocrinology and Metabolism, 79(2), 627-32, August 1994 Abstract
  • Brodie A M, Santen R J, Aromatase and its inhibitors in breast cancer treatment--overview and perspective., Breast Cancer Research and Treatment, 30(1), 1-6, 1994 Abstract
  • Heitjan D F, Manni A, Santen R J, Statistical analysis of in vivo tumor growth experiments., Cancer Research, 53(24), 6042-50, 15 Dec 1993 Abstract
  • Santen R J, Estrogen synthesis inhibitors: from "off the rack" to haute couture [editorial; comment], Journal of Clinical Endocrinology and Metabolism, 77(2), 316-8, August 1993 Abstract
  • Santner S J, Santen R J, Inhibition of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase by antiestrogens., Journal of Steroid Biochemistry and Molecular Biology, 45(5), 383-90, May 1993 Abstract
  • Santner S J, Ohlsson-Wilhelm B, Santen R J, Estrone sulfate promotes human breast cancer cell replication and nuclear uptake of estradiol in MCF-7 cell cultures., International Journal of Cancer, 54(1), 119-24, 22 Apr 1993 Abstract
  • Demers L M, Lipton A, Harvey H A, Kambic K B, Grossberg H, Brady C, Santen R J, The efficacy of CGS 20267 in suppressing estrogen biosynthesis in patients with advanced stage breast cancer., Journal of Steroid Biochemistry and Molecular Biology, 44(4-6), 687-91, March 1993 Abstract
  • Demers L M, Lipton A, Harvey H A, Hanagan J, Mulagha M, Santen R J, The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer., Journal of Steroid Biochemistry and Molecular Biology, 44(4-6), 683-5, March 1993 Abstract
  • Berstein L M, Santner S J, Brodie A M, Koos R D, Naftolin F, Santen R J, Pseudoaromatase in circulating lymphocytes., Journal of Steroid Biochemistry and Molecular Biology, 44(4-6), 647-9, March 1993 Abstract
  • Santner S J, Chen S, Zhou D, Korsunsky Z, Martel J, Santen R J, Effect of androstenedione on growth of untransfected and aromatase-transfected MCF-7 cells in culture., Journal of Steroid Biochemistry and Molecular Biology, 44(4-6), 611-6, March 1993 Abstract
  • Lipton A, Santen R J, Santner S J, Harvey H A, Sanders S I, Matthews Y L, Prognostic value of breast cancer aromatase., Cancer, 70(7), 1951-5, 1 Oct 1992 Abstract
  • Brackett L E, Demers L M, Mamourian A C, Ellenberger C Jr, Santen R J, Moebius syndrome in association with hypogonadotropic hypogonadism., Journal of Endocrinological Investigation, 14(7), 599-607, July 1991 Abstract
  • Santen R J, Demers L M, Lynch J, Harvey H, Lipton A, Mulagha M, Hanagan J, Garber J E, Henderson I C, Navari R M, et al, Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor., Journal of Clinical Endocrinology and Metabolism, 73(1), 99-106, July 1991 Abstract
  • Bardin C W, Swerdloff R S, Santen R J, Androgens: risks and benefits., Journal of Clinical Endocrinology and Metabolism, 73(1), 4-7, July 1991 Abstract
  • Lookingbill D P, Demers L M, Wang C, Leung A, Rittmaster R S, Santen R J, Clinical and biochemical parameters of androgen action in normal healthy Caucasian versus Chinese subjects., Journal of Clinical Endocrinology and Metabolism, 72(6), 1242-8, June 1991 Abstract
  • English H F, Heitjan D F, Lancaster S, Santen R J, Beneficial effects of androgen-primed chemotherapy in the Dunning R3327 G model of prostatic cancer., Cancer Research, 51(7), 1760-5, 1 Apr 1991 Abstract
  • Coen P, Kulin H, Ballantine T, Zaino R, Frauenhoffer E, Boal D, Inkster S, Brodie A, Santen R, An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia [see comments], New England Journal of Medicine, 324(5), 317-22, 31 Jan 1991 Abstract
  • Santen R J, Clinical use of aromatase inhibitors in human breast carcinoma., Journal of Steroid Biochemistry and Molecular Biology, 40(1-3), 247-53, 1991 Abstract
  • Santen R J, Manni A, English H F, Heitjan D, Androgen-primed chemotherapy-experimental confirmation of efficacy., Journal of Steroid Biochemistry and Molecular Biology, 37(6), 1115-20, 20 Dec 1990 Abstract
  • Santen R J, Recent progress in development of aromatase inhibitors., Journal of Steroid Biochemistry and Molecular Biology, 37(6), 1029-35, 20 Dec 1990 Abstract
  • Wild R A, Bartholomew M, Applebaum-Bowden D, Demers L M, Hazzard W, Santen R J, Evidence of heterogeneous mechanisms in lipoprotein lipid alterations in hyperandrogenic women., American Journal of Obstetrics and Gynecology, 163(6 Pt 1), 1998-2005, December 1990 Abstract
  • Kochak G M, Mangat S, Mulagha M T, Entwistle E A, Santen R J, Lipton A, Demers L, The pharmacodynamic inhibition of estrogen synthesis by fadrozole, an aromatase inhibitor, and its pharmacokinetic disposition., Journal of Clinical Endocrinology and Metabolism, 71(5), 1349-5, November 1990 Abstract
  • Santner S J, Levin M C, Santen R J, Estrone sulfate stimulates growth of nitrosomethylurea-induced breast carcinoma in vivo in the rat., International Journal of Cancer, 46(1), 73-8, 15 Jul 1990 Abstract
  • Simons R J, Simon J M, Demers L M, Santen R J, Thyroid dysfunction in elderly hospitalized patients. Effect of age and severity of illness., Archives of Internal Medicine, 150(6), 1249-53, June 1990 Abstract
  • Santen R J, Manni A, Harvey H, Redmond C, Endocrine treatment of breast cancer in women., Endocrine Reviews, 11(2), 221-65, May 1990 Abstract
  • Demers L M, Melby J C, Wilson T E, Lipton A, Harvey H A, Santen R J, The effects of CGS 16949A, an aromatase inhibitor on adrenal mineralocorticoid biosynthesis., Journal of Clinical Endocrinology and Metabolism, 70(4), 1162-6, April 1990 Abstract
  • Lipton A, Harvey H A, Demers L M, Hanagan J R, Mulagha M T, Kochak G M, Fitzsimmons S, Sanders S I, Santen R J, A phase I trial of CGS 16949A. A new aromatase inhibitor., Cancer, 65(6), 1279-85, 15 Mar 1990 Abstract
  • Wild R A, Applebaum-Bowden D, Demers L M, Bartholomew M, Landis J R, Hazzard W R, Santen R J, Lipoprotein lipids in women with androgen excess: independent associations with increased insulin and androgen., Clinical Chemistry, 36(2), 283-9, February 1990 Abstract
  • Lipton A, Harvey H A, Santen R J, Stryker J A, Barnes S G, Walker B K, Dixon R H, Givant E M, Bartholomew M J, Nadjafi C, FAM chemotherapy +/- aminoglutethimide in the treatment of pancreatic carcinoma., European Journal of Surgical Oncology, 16(1), 12-4, February 1990 Abstract
  • Santen R J, Langecker P, Santner S J, Sikka S, Rajfer J, Swerdloff R, Potency and specificity of CGS-16949A as an aromatase inhibitor., Endocrine Research, 16(1), 77-91, 1990 Abstract
  • Santen R J, Clinical use of aromatase inhibitors: current data and future perspectives., Journal of Enzyme Inhibition, 4(2), 79-99, 1990 Abstract
  • Santen R J, Demers L M, Adlercreutz H, Harvey H, Santner S, Sanders S, Lipton A, Inhibition of aromatase with CGS 16949A in postmenopausal women., Journal of Clinical Endocrinology and Metabolism, 68(1), 99-106, January 1989 Abstract
  • Masamura S. Santner SJ, Heitjan DF, Santen RJ Estrogen deprivation causes estradiol hypersensitivity in human breast Cancer cells J. Clin. Endocrinol Metabol Vol. 80, Pages: 2918-2925, 1995
  • Santen RJ, et al. Stromal spindle cells contain aromatase in human breast tumors. J. Clin. Endocrinol. Metabol. Vol. 79, Pages 627-632; 1994
  • Santen, RJ et al. Endocrine treatment of breast cancer in women Endocrinol. Rev. Vol. 11, Pages: 221-265; 1990
  • Santen RJ et al. A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer New England Journal of Medicine Vol. 305; Pages: 545-551; 1981
  • Santen, RJ Is aromatization of testosterone to estradiol required for inhibition of LH secretion in men? J. Clin. Invest Vol. 56; Pages: 1555-1563, 1975

Profile Details

Last Updated: 8/3/1998

COS Expertise ID #406308
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