A major research focus of this laboratory is to investigate the roles of aromatase in breast cancer development. In estrogen-dependent breast tumors, estrogen binds to the estrogen receptor protein and induces the expression of peptide growth factors that are responsible for the proliferative responses of cancer cells.
Aromatase is an enzyme that converts androgen to estrogen. Since aromatase is the enzyme responsible for the synthesis of estrogen, and estrogen can have a major effect in the development of breast cancer, an abnormal expression of aromatase in breast cancer cells and/or surrounding adipose stromal cells may have a significant influence on breast tumor development and growth in cancer patients. Aromatase is expressed at higher levels in human breast cancer tissue than in normal breast tissue, as measured by various biochemical assays. Studies are being conducted in this laboratory to analyze the tissue specific regulation of the promoter elements in the human aromatase gene. In addition, structure-function studies are performed in this laboratory to characterize the structural features of the active site of aromatase.
Since the suppression of estrogen formation (by aromatase inhibitors) is considered an important breast cancer treatment strategy, it is vital that the structural nature of the inhibitor-binding site of aromatase be determined. We have succeeded in the expression a purification of functionally active human aromatase from E. coli. Efforts are being made to determine the three-dimensional structures of substrate/inhibitor-bound enzymes. This information will be critical for the design of potent and selective aromatase inhibitors for breast cancer treatment.
During the last five years, aromatase inhibitors have been demonstrated to be superior to tamoxifen with the treatment of hormonal dependent breast cancer. While these new generation of aromatase inhibitors are shown to be useful in the treatment of hormonal responsive breast cancer, resistance to such endocrine therapy still develop. Through collaboration with Yate-Ching Yuan, Ph.D., (Bioinformatics), we are carrying out gene expression array experiments on aromatase inhibitor-responsive as well as resistant cell lines that have been generated in our laboratory. We plan to identify and functionally confirm the roles of genes involved in resistance.
It is hypothesized that these studies will produce valuable molecular information regarding the mechanisms of aromatase inhibitor resistance, and the information will help design approaches to reduce resistance and improve the efficacy of aromatase inhibitor treatments of breast cancer. By reviewing our results generated from our preclinical studies, we have started working with George Somlo, M.D., (Medical Oncology) in the design of new therapeutic approaches to treat aromatase inhibitor resistant breast cancer.
We also conduct research to determine how environmental chemicals modulate the activity and expression of aromatase in human tissue. Experiments are being conducted to provide a molecular and mechanistic basis as to how phytochemicals and organochlorine compounds affect estrogen biosynthesis (i.e., aromatase function) in women. Together with Yuan, computer-assisted screening methods have been developed to search for environmental chemicals that modulate the activity of aromatase.
In addition, our laboratory has found that grapes, mushrooms and red wine contain chemicals that can suppress aromatase activity. Therefore, a diet that includes grapes, mushrooms and red wine would be considered preventative against breast cancer. We are purifying and characterizing these natural anti-aromatase chemicals and evaluating their in vivo effects using animal experiments. The active chemicals in grapes and red wine have been found to be procyanidin dimmers that are present at high concentrations in grape seeds. Melanie Palomares, M.D., (Clinical Cancer Genetics), Jeffrey Weitzel, M.D., (Clinical Cancer Genetics), Tim Synold, Pharm.D., (Experimental Therapeutics) and this laboratory have collaborated and initiated a grape seed extract clinical trial based on the chemoprevention studies against breast cancer using grape seed extract.
Furthermore, we have found that mushrooms contain chemicals that act as inhibitors of steroid 5-alpha reductase. Androgen plays a critical role in prostate cancer development. In the prostate, testosterone (an androgen) is converted to dihydrotestosterone (DHT), an androgen that is even more potent than testosterone. This conversion is catalyzed by the enzyme steroid 5-alpha reductase. An elevation of the steroid 5-alpha reductase activity in the prostate may cause benign prostate hyperplasia (a common problem in older men) and also promote the growth of prostate cancer. Inhibitors of steroid 5-alpha reductase have been developed to treat these prostate diseases. We are purifying the chemicals from mushrooms and designing animal experiments to evaluate the use of these phytochemicals as drugs in the prevention and/or treatment of prostate cancer.
Since the summer of 2004, Chen and 27 other investigators have initiated an effort to develop a chemoprevention research program at City of Hope. Through biweekly meetings, these Beckman researchers and clinicians exchange research information and ideas. Four research areas have recently been chosen to focus on. The immediate goal is to generate preliminary results in these new target areas that will lead to the development of multidiscipline translational chemoprevention research projects at our institution.
Recently, we have found that nuclear receptors can modulate the expression of aromatase. One of the receptors identified is estrogen-related receptor. Using computer-assisted high throughput screening approach, Yate-Ching Yuan, Ph.D., (Bioinformatics) and this laboratory have identified agonists and antagonists of this orphan nuclear receptor.
Furthermore, we have identified a novel co-regulatory protein (i.e., PNRC) that modulates nuclear receptor-mediated and Ras/MAP kinase-mediated pathways by interacting with nuclear receptors and GRB2. Extensive molecular studies are currently being performed to determine the molecular features of this protein for its interaction with proteins in the signal transduction pathways. To better understand the function of this co-regulatory protein, PNRC knockout mice have been generated and are characterized in this laboratory.
In addition, we have initiated a collaborative project with David Heber, M.D. (UCLA) to evaluate the effects of herbal supplements in vitro and in vivo. Pomegranates and blueberry have been found to contain phytochemicals that can suppress the development of different types of breast cancer in mice. Experiments are being performed to determine the chemopreventive mechanisms of these phytochemicals.
