Breast Cancer Translation Research
Shiuan Chen, Ph.D., was one of the three investigators who originally isolated the full-length human aromatase cDNA clones. Aromatase is an enzyme that converts androgen to estrogen. Aromatase inhibitors (AIs) are important drugs to treat estrogen-dependent breast cancer. Approximately 60percent of premenopausal and 75 percent of postmenopausal breast cancer patients have estrogen-dependent carcinomas.
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. During the last 15 years, aromatase inhibitors (AIs) have been demonstrated to be superior to tamoxifen for the treatment of hormonal dependent breast cancer. While this new generation of aromatase inhibitors is shown to be useful in the treatment of hormonal responsive breast cancer, resistance to such endocrine therapy still develops. Through collaboration with Yate-Ching Yuan, Ph.D., (Bioinformatics), we are carrying out gene expression array experiments on AI-responsive as well as resistant cell lines that have been generated in our laboratory. We are identifying and functionally confirming the roles of genes involved in resistance.
These studies will produce valuable molecular information regarding the mechanisms of AI resistance, and the information will help design approaches to reduce resistance and improve the efficacy of AI treatments of breast cancer. Furthermore, our model systems are valuable to test new drugs against endocrine therapy resistance. We are working with several medical and translational research colleagues (Joanne Mortimer, M.D. , Yuan Yuan, M.D., Ph.D., George Somlo, M.D., Laura Kruper, M.D., Courtney Vito, M.D.,Paul Frankel, Ph.D., Tim Synold, Pharm.D.), and Ned Newman, Ph.D. ) to carry preclinical studies in our laboratories and then to design new therapeutic approaches to treat AI resistant breast cancer.
Chemoprevention and Superfood Research Program
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 Research Institute of City of Hope 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.
Our laboratory has found that grapes, mushrooms and pomegranate contain chemicals that can suppress aromatase activity. Therefore, a diet containing these "superfoods" 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 have been found to be procyanidin dimers that are present at high concentrations in grape seeds. Melanie Palomares, M.D., M.S., (Population Sciences), 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 and a mushroom clinical trial based on the chemoprevention studies against breast cancer performed in our laboratory. In addition, experiments have been carried out to show that blueberry contains phytochemicals that can suppress the proliferation and migration of triple negative breast cancer in cell culture and animals.
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. Animal experiments have been performed to evaluate the use of these phytochemicals as drugs in the prevention and/or treatment of prostate cancer. One clinical trial designed, based Chen’s findings, is being carried out at City of Hope with Przemyslaw Twardowski, M.D. (Medical Oncology) to evaluate the protective effect of mushroom chemicals against PSA increase in prostate cancer patients. The trial has resulted in two patients with complete response, two patients with partial response, and eight patients with stable PSA response. A recent study in the Chen laboratory has revealed that the intake of mushrooms may reduce the incidence of metabolic diseases such as fatty liver and insulin resistance.
In 2014, with a $2.5 million gift from the Panda Charitable Foundation, a Program in Natural Therapies has been established at City of Hope. This fund supports three lines of research to investigate natural products’ abilities to fight against cancer. Chen is investigating how the foods themselves can improve outcomes of treatment-resistance breast cancer. In addition, the Chen laboratory is generating patient-derived xenograft (PDX) models for novel treatment of breast cancer.
Endocrine Disruptor Research
We are also conducting 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 (e.g., aromatase function) in women. Research from Chen’s and other laboratories have revealed that estrogen receptors (ER), aromatase, and ERR are key players in breast cancer promotion and in cancer recurrence following endocrine treatment. Furthermore, proof-of-concept studies have revealed that these proteins are targets of endocrine disruptors. Based on these observations, we hypothesize that environmental chemicals will play critical roles in modulating breast cancer through ER, aromatase and ERR. We have developed a high throughput screening system (AroER Tri-Screen™) for identifying chemicals targeting ER and aromatase. The goal of this research is to develop screening assays for identifying and testing chemicals with relevance to known and suspected causes of estrogen-dependent breast cancer. Our collaborators include Yate-Ching Yuan, Ph.D. (Bioinformatics Core), Xiwei Wu, M.D., Ph.D. (Integrative Genomics Core), Christina Teng, Ph.D. (National Institute of Environmental Health Sciences), Menghang Xia, Ph.D., and Ruiling Huang, Ph.D. (National Center for Advancing Translational Sciences), Sandra Finestone, Psy.D. (Hope Wellness Center, Costa Mesa, California) and Kimlin Tam Ashing, Ph.D. (Population Sciences). Furthermore, we are collaborating with Myrto Petreas, Ph.D. (California Department of Toxic Substances Control) and Peggy Reynolds, Ph.D. (Cancer Prevention Institute of California) for the evaluation of estrogenic activity in human serum using AroER Tri-Screen.