Dr. Stephen H. Safe, Distinguished Professor
Director, Center for Environmental and Genetic Medicine
Institute of Biosciences and Technology
Texas A&M University Health Science Center
ssafe@cvm.tamu.edu

Lab Personnel

Research in Dr. Safe's 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 a (ERa) and ERb by endocrine disruptors. A brief description of the individual projects is indicated below.

(a) Mechanism of aryl hydrocarbon (AhR)-ERa crosstalk in breast cancer cells

Research in the Safe laboratory has demonstrated that ligands that activate the AhR inhibit ERa signaling in breast and endometrial cancer cells. The mechanisms of inhibitory AhR-ERa crosstalk are complex and current studies are investigating multiple aspects of these interactions including AhR ligand activation of proteasome-dependent degradation of ERa and displacement of ER/Sp1 from GC-rich promoter sequences.

(b) Mechanisms of growth factor (GF) activation of genes and non-genomic pathways of estrogen (E2) action in breast cancer cells

The mechanisms associated with E2/GF-induced tumor cell growth are complex and both nuclear ERa-dependent and nuclear ERa-independent pathways are involved. The importance of these pathways also depends on gene/gene promoters and cell context, and non-genomic kinase pathways may be important new targets for drug action. In this study, we are investigating the domains of ERa required for activation of non-genomic pathways of E2 action and the specific downstream genes that are targeted.

(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 ERa/Sp1 in regulating estrogen-responsive genes in breast cancer cells and in vivo models

A novel mechanism of transcriptional activation of genes by E2 in breast cancer cells involves interaction of ERa/Sp1 with selected GC-rich Sp1 binding sites in target gene promoters, and ERa/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 coactivatin of ERa/Sp1 by different nuclear factors and their mechanism of action as well as development of mouse models for studying hormone activation of ERa/Sp1 in multiple tissues.

(e) Mechanisms of ligand structure-dependent activation of ERa, ERb 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 ERa and ERa) and their interactions with other intracellular receptors.

(f) C-substituted DIM analogs as a new class of PPARg 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 PPARg 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.