- Zalk Missouri Professor of Tumor Angiogenesis
- Investigator, Dalton Cardiovascular Research Center
Role of Steroid Hormones in Tumor Angiogenesis; Molecular mechanisms of steroid hormone/anti-hormone action.
The main aim of our laboratory is to identify steroid hormone dependent molecular targets that can be utilized for anti-angiogenic therapy of endocrine dependent disease such as the breast, uterine, and prostate cancer.
Formation of new blood vessels, or angiogenesis, is crucial for normal processes such as embryonic development, wound healing, and endometrial regeneration following menstruation. Angiogenesis is also essential for tumor growth, and metastasis. An emerging field in cancer therapeutics is the targeting of new blood vessels to curtail tumor growth. Our laboratory is currently focusing on the role of steroid hormones, clinically relevant anti-hormones, and endocrine-disruptors to understand the basic mechanisms involved in hormone driven angiogenesis in breast, and uterine tissue. We are currently focusing on the role of estrogens, progestins, and their nuclear receptors in controlling the expression of potent angiogenic growth factors (e.g VEGF and its receptors) at both molecular and cellular level.
Another focus of the laboratory is to investigate the molecular mechanisms of steroid hormone action at the level of gene transcription. We are especially interested in the role of natural and synthetic ligands that have diverse biological effects in different target tissues (e.g SERMS such as tamoxifen). Many synthetic ligands (agonists /antagonists) are consumed by millions of women all over the world for oral contraception, hormone replacement therapy, or treatment of breast cancer. Consumption of some of these ligands lead to increased risk of breast and/or uterine abnormalities, including cancer. We anticipate that understanding the molecular basis/pharmacology of ligand-nuclear receptor interactions will allow development of better therapeutic modalities for treatment of hormone dependent tumors, as well as endometriosis, osteoporosis, and infertility.
Hyder, S. M., Stancel, G. M., Chiappetta, C., Murthy, L., Boettger-Tong,H. L. and Makela, S. (1996). Uterine expression of vascular endothelial growth factor is increased by estradiol as well as tamoxifen. Cancer Res. 56:3954-3960.Hyder, S. M., Chiappetta, C., Murthy, L. and Stancel, G. M. (1997). Selective inhibition of estrogen regulated genes in vivo by pure antiestrogen ICI 182,780. Cancer Res. 57:2547-2549.
Hyder, S. M., Murthy, L. and Stancel, G. M. (1998). Progestin regulation of vascular endothelial growth factor in human breast cancer. Cancer Res. 58: 392-395.
Nawaz, Z., Stancel, G. M., and Hyder, S. M. (1999). Pure Antiestrogen ICI 182,780 Inhibits Progestin-Induced Transcription. Cancer Res. 59:372-376.
Hyder, SM, Chiappetta, C. and Stancel, GM (1999). Interaction of Estrogen Receptors alpha and beta with the naturally occuring estrogen response elements. Biochemical Pharmacology 57:597-601
Hyder, S. M., Chiappetta, C. and Stancel, G. M. (1999). The synthetic estrogen 17 alpha-ethinyl estradiol induces a similar pattern of uterine gene expression as the endogenous estrogen 17 beta-estradiol. J. Pharm. Expt. Therapeutics 290:740 747.
Hyder, S. M., Chiappetta, C. and Stancel, G. M. (2000) Induction of the Angiogenic Factor VEGF in the Uterus by the Anti-progestin Onapristone. Cancer Lett 156:101 107.
Hyder, S. M., Nawaz, Z., Chiappetta, C. and Stancel G. M. (2000) Identification of functional estrogen response elements in the gene coding for the potent angiogenic factor vascular endothelial growth factor. Cancer Res. 60:3183-3190
Nephew, K. P. Ray, S., Hlaing, M., Ahluwalia, A., Wu, S. D., Long, X., Hyder, S. M., and Bigsby, R. M. (2000). Expression of steroid hormone receptor co-activators in the uterus of sexually immature and mature rats. Biol of Reproduction 63: 361-367.
Hyder, S. M., Huang, J. C., Nawaz, Z., Boettger-Tong, H., Makela, S., Chiappetta, C. and Stancel, G. M. (2000). Regulation of VEGF expression by Estrogens and Progestins. Env. Health Perspective. 108 Suppl 5:785 790.
Krumenacker, J. S., Hyder, S. M. and Murad, F. (2001). Estradiol rapidly inhibits soluble guanylyl cyclase expression in rat uterus. Proc Natl Acad Sci. 98: 717-722.
Hyder, S. M., Chiappetta, C. and Stancel, G. M. (2001) Pharmacological and endogenous progestins induce vascular endothelial growth factor expression in human breast cancer cells. Int J Cancer 92:469 473.
Hyder, S. M. and Stancel, G. M. (2002) Pure antiestrogen ICI 182,780 inhibits progesterone induced VEGF induction in breast cancer cells. Cancer Lett 181: 47-53.
Hyder, S. M. (2002). The role of steroid hormones on the regulation of vascular endothelail growth factor. Am J Pathology. 161: 345-346
Uray, I., Liang, Y. and Hyder, S. M. (2004). Estradiol Down-regulates CD36 expression in human breast cancer cells. Cancer Lett. 207: 101-107.
Wu, J., Richer, J., Horwitz, K. B. and Hyder, S. M. (2004). Progestin-dependent induction of VEGF in uman breast cancer cells: preferential regulation by progesterone receptor B. Cancer Res 64:2238-2244.
Wu, J., Brandt, S. and Hyder, S. M. (2005) Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced VEGF levels in human breast cancer cells Molecular Endocrinology 19:312-326
Liang, Y., Wu, J. and Hyder, S. M. (2005). p53-dependent inhibition of progestin-induced VEGF expression in human breast cancer cells. J. Steroid Biochemistry and Molecular Biology 93:173-182.
Liang, Y. and Hyder, S.M. (2005) Proliferation of Endothelial and Tumor Epithelial Cells by Progestin-Induced VEGF from Human Breast Cancer Cells: Paracrine and Autocrine Effects. Endocrinology 146; 3632-3641.
Wu, J., Liang, Y., Nawaz, Z. and Hyder, S. M. (2005). ICI 182,780 (Faslodex) exhibits partial progestin-like activity in human breast cancer cells expressing increased levels of PRB. Int. J .Oncol. 27:1647-1659.
Zhou, W., Liu, Z., Wu, J., Liu, J., Hyder, S. M., Antoniou, E. and Lubahn, D. B. (2006) Identification and partial characterization of two novel splicing isoforms of human ERR-beta. J Clin Endo Metab. 91:569-79.
Benakanakere, I., Besch-Williford, C., Schnell, J., Brandt, S., Molinolo, A., and Hyder, S. M. (2006) Natural and synthetic progestins accelerate 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mammary tumors and increase angiogenesis in Sprague-Dawley rats. Clin Cancer Res 12::4062-4071.
Hyder, S.M. (2006) Sex-steroid regulation of vascular endothelial growth factor in breast cancer. End Related Cancer. 13: 667-687
Carroll, C. E., Elersieck, M. R. and Hyder, S. M. (2008). Curcumin inhibits medroxyprogesterone acetate induced VEGF from T47-D human breast cancer cells. Menopause 15:570-574.
Benakanakere, I., Besch-Williford, C., Elersieck, M. R.and Hyder, S. M. (2009). Regression of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced and progestin-accelerated mammary tumors in Sprague-Dawley rats by PRIMA-1: A pilot study. End Related Cancer 16:85-98.
Liang, Y., Besch-Williford C. and Hyder, S. M., (2009) PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein. Int J Oncology 35:1015-1023.
Carroll, C., Besch-Williford C., Benakanakere, I., Elersieck, M. R. and Hyder, S. M. (2010). Curcumin delays development of DMBA-induced progestin-accelerated mammary tumors. Menopause. 17:178-184.
Liang, Y., Benakanakere, I., Besch-Williford, C. B., Hyder, R. S., Ellersieck, M., Hyder, S. M. (2010). Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice. Menopause 17: 1040-1047.
Benakanakere, I., Carroll, C. E., Besch-Williford, C and Hyder, S. M. (2010). Synthetic progestins differentially promote or prevent DMBA-induced mammary tumors in Sprague-Dawley rats. Cancer Prevention Res 3:1157-1167.
Liang, Y., Besch-Williford., Benakanakere, I., Thorpe, P. E. and Hyder, S. M. (2011) Targeting mutant p53 protein and the tumor vasculature: An effective combination therapy for advanced breast tumors. Breast Cancer Res Treat 125: 407-420.
Mafuvadze, B., Benakanakere, I., Lopez, F., Besch-Williford, C., Ellersieck, M. R. and Hyder, S. M. (2011) Apigenin prevents development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats. Cancer Prevention Res 4: 1316-1324. PMC3151306
Mafuvadze, B., Liang, Y., Besch-Williford, C. and Hyder, S. M. (2012) Apigenin induces apoptosis and blocks growth of medroxyprogesterone acetate-dependent BT-474 xenograft tumors. Hormones and Cancer, 3:160–171
Carroll, C., Benakanakere, I., Liang, Y., Besch-Williford, C and Hyder, S.M. (2013) An anticancer agent YC-1 suppresses progestin-stimulated VEGF in breast cancer cells and arrests breast tumor development. Int. J. Oncology, 42: 179-187.