Stephen H. Safe, PhD
Joint Distinguished Professor
Education and Post-Graduate Training
Dr. Stephen H. Safe is a Distinguished Professor of Veterinary Physiology and Pharmacology and of Biochemistry and Biophysics. He holds the Sid Kyle Chair in Toxicology. He received his BSc and MSc from Queen’s University in 1962 and 1963, respectively. He obtained his DPhil from Oxford University in 1965. His postdoctoral research was at Oxford University and Harvard University from 1966 to 1968. Safe joined the faculty at Texas A&M University in 1981. He has been with the Institute of Biosciences & Technology at Texas A&M Health Science Center since 2002 where he is the Director of the Center for Translational Environmental Health Research. He became a joint faculty member in the Department of Molecular & Cellular Medicine in 2009.
Research in the Safe Laboratory is primarily focused on the molecular biology of hormone/growth factor-induced gene expression in breast cancer cells, the development of new mechanism-based drugs for treatment of breast and other cancers and the differential activation of estrogen receptor α (ERα) and ERβ by endocrine disruptors. A brief description of the individual projects is indicated below.
(a) Mechanism of aryl hydrocarbon (AhR)-ERα crosstalk in breast cancer cells
Research in the Safe laboratory has demonstrated that ligands that activate the AhR inhibit ERα signaling in breast and endometrial cancer cells. The mechanisms of inhibitory AhR-ERα crosstalk are complex and current studies are investigating multiple aspects of these interactions including AhR ligand activation of proteasome-dependent degradation of ERα and displacement of ER/Sp1 from GC-rich promoter sequences.
(b) Anticancer Drugs that Target Sp transcription Factors
Research in the Safe laboratory has identified a new class of mechanism- based drugs that downregulate Sp transcription factors that are overexpressed in tumor but not non-tumor tissue. The agents are highly effective against multiple tumor types and the mechanisms involve suppression of microRNAs.
(c) Development of selective AhR modulators (SAhRMs) for treatment of breast and endometrial cancers
A high percentage of early stage mammary tumors are ER-positive, and many of these patients respond to antiestrogen or endocrine therapy with drugs such as tamoxifen which has been successfully used for treatment of several million women with breast cancer. Unfortunately, resistance to tamoxifen can develop in some patients and there is now increasing concern that long term use of this drug increases the risk for endometrial cancer.
Therefore, it is imperative to develop new drugs that can be used alone or in combination therapy (e.g. with tamoxifen) for treatment of hormone-dependent tumors. Our studies have identified alternate-substituted alkyl PCDFs and ring-substituted diindolylmethanes (DIMs) as new mechanism-based drugs for treatment of ER-positive and ER-negative breast cancers, and the efficacy of these compounds alone and in combination with other drugs such as tamoxifen is being investigated.
(d) The role of ERα/Sp1 in regulating estrogen-responsive genes in breast cancer cells and in vivomodels
A novel mechanism of transcriptional activation of genes by E2 in breast cancer cells involves interaction of ERα/Sp1 with selected GC-rich Sp1 binding sites in target gene promoters, and ERα/Sp1 action plays an important role in hormonal regulation of gene expression in breast cancer cells and possibly in murine models. Currently, we are investigating coactivation of ERα/Sp1 by different nuclear factors and their mechanism of action as well as development of mouse models for studying hormone activation of ERα/Sp1 in multiple tissues.
(e) Mechanisms of ligand structure-dependent activation of ER&apha;, ERβ and other hormone receptors
Standardized screening and testing for industrial-derived estrogenic chemicals (xenoestrogens) will provide assay-specific potency data but may not be predictive for their tissue-specific estrogen receptor (ER) agonist or antagonist activities. Based on results of preliminary studies with bisphenol A and other analogs, we are investigating the hormonal activity of different structural classes of xenoestrogens and naturally-occurring estrogenic compounds and their activation of non-genomic and classical genomic estrogenic pathways (through ERα and ERβ) and their interactions with other intracellular receptors.
(f) C-substituted DIM analogs as a new class of PPARγ agonists
Recent studies in this laboratory have identified a series of methylene (C)-substituted DIM analogs that inhibit growth of breast, endometrial, pancreatic, prostate, lung and ovarian cancer cell growth. These compounds activate PPARγ and downregulate cyclin D1 protein in cancer cell lines and the overall mechanism of action of C-substituted DIMs and their application for cancer chemotherapy is currently being investigated.
- Jutooru, I., Chadalapaka, G., Chintharlapalli, S., Papineni, S. and Safe, S. Induction of apoptosis and nonsteroidal anti-inflammatory drug-activated gene 1 in pancreatic cancer cells by a glycyrrhetinic acid derivative. Mol. Carcinog. 48:692-702, 2009.
- Papineni, S., Chintharlapalli, S., Abdelrahim, M., Lee, S.O., Burghardt, R., Abudayyeh, A., Baker, C., Herrera, L. and Safe, S. Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. Carcinogenesis 30:1193-1201, 2009.
- Zhang, S., Lei, P., Liu, X., Li, X., Walker, K., Kotha, L., Rowlands, C. and Safe, S. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr. Relat. Cancer 16:835-844, 2009.
- Chintharlapalli, S., Papineni, S., Abdelrahim, M., Abudayyeh, A., Jutooru, I., Chadalapaka, G., Wu, F., Mertens-Talcott, S., Vanderlaag, K., Cho, S.D., Smith, R. 3rd and Safe, S. Oncogenic microRNA-27a is a target for anticancer agent methyl 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate in colon cancer cells. Int. J. Cancer 125:1965-1974, 2009.
- Lee, S.O., Chintharlapalli, S., Liu, S., Papineni, S., Cho, S.D., Yoon, K. and Safe, S. p21 expression is induced by activation of nuclear nerve growth factor-induced Bα (Nur77) in pancreatic cancer cells. Mol. Cancer Res. 7:1169-1178, 2009.
- Sreevalsan, S., Jutooru, I., Chadalapaka, G., Walker, M. and Safe, S. 1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane and related compounds repress survivin and decrease γ-radiation-induced survivin in colon and pancreatic cancer cells. Int. J. Oncol. 35:1191-1199, 2009.
- Da Costa, C.A., Sunyach, C., Giaime, E., West, A., Corti, O., Brice, A., Safe, S., Abou-Sleiman, P.M., Wood, N.W., Takahashi, H., Goldberg, MS, Shen, J. and Checler, F. Transcriptional repression of p53 by parkin and impairment by mutations associated with autosomal recessive juvenile Parkinson's disease. Nat. Cell Biol. 11:1370-1375, 2009.
- Choi, K.H., Kim, H.K., Kim, H.J., Choi, E.S., Shin, J.A., Lee, S.O., Chintharlapalli, S., Safe, S. Abdelrahim, M., Kong, G., Choi, H.S., Jung, J.Y., Cho, H.T., Cho, N.P. and Cho, S.D. The p38 MAPK pathway is critical for 5,5'-dibromodiindolylmethane-induced apoptosis to prevent oral squamous carcinoma cells. Eur. J. Cancer Pres. 19:153-159, 2010.
- Liu, X., Abdelrahim, M., Abudayyeh, A., Lei, P. and Safe, S. The nonsteroidal anti-inflammatory drug tolfenamic acid inhibits BT474 and SCBR3 breast cancer cell and tumor growth by repressing erbB2 expression. Mol. Cancer Therap. in press, 2010.
- Guo, J., Chintharlapalli, S., Lee, S., Cho, S.D., Lei, P., Papineni, S. and Safe, S. Peroxisome proliferator-activated receptor γ-dependent activity of indole ring-substituted 1,1-bis(3'-indolyl)-1-(p-biphenyl)methanes in cancer cells. Cancer Chemother. Pharmacol. in press, 2010.
- Colon, J., Basha, M.R., Madero-Visbal, R., Konduri, S., Baker, C.H., Herrera, L.J., Safe, S., Sheikh-Hamad, D., Abudayyeh, A., Alvarado, B. and Abdelrahim, M. Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cell growth and tumor formation in orthotopic mice. Invest. New Drugs in press, 2010.
- Cho, S.D., Lee, S.O., Chintharlapalli, S., Abdelrahim, M., Khan, S., Yoon, K., Kamat, A. and Safe, S. Activation of nerve growth factor-induced Bα by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth. Mol. Pharmacol. in press, 2010.