Richard J. Santen, MD
Graduate School: University of Michigan
Primary Appointment: Professor, Medicine, Endocrinology and Metabolism
Expression of aromatase and role of estrogen in breast cancer; tissue selective estrogen complex (TSEC) therapy formenopause.
Email Address: firstname.lastname@example.org
Women with estrogen-receptor-positive breast cancers frequently respond initially to inhibition of estrogen secretion or action, but later relapse. Secondary therapies designed to further lower estrogen levels induce additional remissions, but progression to a hormone-refractory state invariably follows. The mechanisms mediating these secondary responses and later progression are incompletely understood. Based upon our prior studies, we postulate that tumor cells can adapt to conditions of estrogen deprivation by developing enhanced sensitivity to estrogens. Using a model system of long- term estradiol withdrawal, we have directly demonstrated the ability of cells to develop hypersensitivity to estradiol both in vitro and in vivo.
Our studies indicated that hypersensitivity is not mediated at the level of estrogen receptor transcription. Rather, adaptation to estradiol deprivation results in overproduction of growth factor signaling pathways, which interact with receptor-mediated events to enhance estradiol sensitivity. Cross talk between estrogen-signaling and growth-factor-signaling pathways occurs at both upstream and downstream levels. These interactions affect not only cell proliferation but also cell death. We plan to further examine these adaptive mechanisms and then exploit them to develop novel therapeutic approaches to the treatment of breast cancer. These novel approaches involve combined simultaneous blockade of growth factor and estrogen pathways, as well as stimulation of apoptosis with pulse estradiol administration.
Song Y, Santen RJ, Wang JP, Yue W. Inhibitory effects of a bazedoxifene/conjugated equine estrogen combination on human breast cancer cells in vitro. Endocrinology. 2013 Feb;154(2):656-65. doi: 10.1210/en.2012-2038. Epub 2012 Dec 19. PubMed PMID: 23254198.
Yue W, Yager JD, Wang JP, Jupe ER, Santen RJ. Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis. Steroids. 2013 Feb;78(2):161-70. doi: 10.1016/j.steroids.2012.11.001. Epub 2012 Nov 20. PubMed PMID: 23178278.
Song Y, Santen RJ, Wang JP, Yue W. Effects of the conjugated equine estrogen/bazedoxifene tissue-selective estrogen complex (TSEC) on mammary gland and breast cancer in mice. Endocrinology. 2012 Dec;153(12):5706-15. doi: 10.1210/en.2012-1583. Epub 2012 Oct 15. PubMed PMID: 23070546.
Eggleston E, Liu Z, Mirmira RG, Silva CM, Shu J, Santen RJ. Insights into mentorship for endocrinologists. J Clin Endocrinol Metab. 2012 Nov;97(11):3891-6. doi: 10.1210/jc.2012-2215. Epub 2012 Sep 11. PubMed PMID: 22969142; PubMed Central PMCID: PMC3485610.
Santen RJ, Yue W, Heitjan DF. Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy. Cancer Epidemiol Biomarkers Prev. 2012 Jul;21(7):1038-48. doi: 10.1158/1055-9965.EPI-12-0043. Epub 2012 May 14. PubMed PMID: 22586072.
Kim T, Park H, Yue W, Wang JP, Atkins KA, Zhang Z, Rogan EG, Cavalieri EL, Mohammad KS, Kim S, Santen RJ, Aiyar SE. Tetra-methoxystilbene modulates ductal growth of the developing murine mammary gland. Breast Cancer Res Treat. 2011 Apr;126(3):779-89. doi: 10.1007/s10549-010-1301-5. Epub 2010 Dec 18. PubMed PMID: 21170676.
Santen RJ. Clinical review: Effect of endocrine therapies on bone in breast cancer patients. J Clin Endocrinol Metab. 2011 Feb;96(2):308-19. doi: 10.1210/jc.2010-1679. Epub 2010 Dec 8. Review. PubMed PMID: 21147884.
Aiyar SE, Park H, Aldo PB, Mor G, Gildea JJ, Miller AL, Thompson EB, Castle JD, Kim S, Santen RJ. TMS, a chemically modified herbal derivative of resveratrol, induces cell death by targeting Bax. Breast Cancer Res Treat. 2010 Nov;124(1):265-77. doi: 10.1007/s10549-010-0903-2. Epub 2010 May 20. PubMed PMID: 20490654.
Li Y, Wang JP, Santen RJ, Kim TH, Park H, Fan P, Yue W. Estrogen stimulation of cell migration involves multiple signaling pathway interactions. Endocrinology. 2010 Nov;151(11):5146-56. doi: 10.1210/en.2009-1506. Epub 2010 Sep 22. PubMed PMID: 20861240; PubMed Central PMCID: PMC2954727.
Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M, Gower BA, Henderson VW, Jarjour WN, Karas RH, Kleerekoper M, Lobo RA, Manson JE, Marsden J, Martin KA, Martin L, Pinkerton JV, Rubinow DR, Teede H, Thiboutot DM, Utian WH; Endocrine Society. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010 Jul;95(7 Suppl 1):s1-s66. doi: 10.1210/jc.2009-2509. Epub 2010 Jun 21. Review. PubMed PMID: 20566620.