Influence of environmental endocrine disruptors and carcinogenesis - Project Summary/Abstract Breast cancer affects many women in their lifetime. A major challenge remains how to reduce breast cancer risk as well as to understand what causes breast cancer. Two-thirds of breast cancer diagnosed in patients belong to estrogen receptor (ER)-positive breast cancer. Many chemicals, with similar structure to estrogen, have been suggested to mimic the biological functions of estrogen, potentially contributing to the initiation or progression of breast cancer. Environmental estrogenic endocrine disruptor contaminants, such as bisphenols, phthalates and zeranols, have been known to have estrogenic activity in cell culture and animal models. However, the impact of endocrine disruptors on breast cancer development in humans remains unclear. We hypothesize that endocrine disruptors, by increasing breast cancer stem cells and altering tumor metabolism, promote the development of breast cancer. The objectives of this project are to determine impact of endocrine disruptors in breast cancer development and to understand mechanisms of endocrine disruptors in alteration of cancer stem cells and metabolome leading to accelerating ER-positive breast cancer. We propose two Specific Aims as follows. In Aim 1, using the estrogen sensitive ACI strain, we will investigate the impact of endocrine disruptors on the mammary gland proliferation in vivo. We will test three representative classes of common environmental endocrine disruptors, bisphenols, phthalates and zeranols for this Aim. In Aim 2, we will determine endocrine disruptors-induced alteration of breast cancer stem cells and cell metabolism in the ER-positive breast cancer model. MCF-7 mammosphere culture and MCF-7 xenografted tumor models will be utilized to investigate the role of endocrine disruptors in enhancing cancer stem cells and altering tumor metabolism in vitro and in vivo. We will test three representative classes of endocrine disruptors, bisphenols, phthalates and zeranols in vitro. Selected endocrine disruptors will be further evaluated for in vivo tumor studies. Endocrine disruptors have long been suggested for its potential role in promoting cancer development and progression. This project seeks to understand the mechanism of endocrine disruptors in the mammary tumorigenesis by focusing on cancer stem cells and metabolism shift. Environmental factors and lifestyle have led to significant changes in breast cancer risks. Our study with endocrine disruptors could provide the valuable link between environmental exposures and human health.
