The developing mammary gland (MG) is vulnerable to environmental and lifestyle risk factors that increase breast cancer (BC) burden in later adulthood. Therefore, optimizing BC prevention and care requires a lifespan approach to identify specific early life risk factors, to understand these risk factors? underlying molecular mechanisms in promoting cancer risk, and to design appropriate interventions that reduce BC in adulthood. Using a Sprague-Dawley rat model of human BC, we have established a dynamic and successful transdisciplinary collaboration among a breast cancer biologist, an endocrinologist, and a biopsychologist to understand how adverse early life exposures lead to increased mammary cancer risk in adulthood. We find that glucocorticoid (GC) reactivity to everyday stressors is heighted by social isolation in puberty and young adulthood and is associated with increased adult mammary cancer burden. Moreover, heightened GC reactivity during puberty impairs ductal development and increases mammary stem cell populations, two characteristics that have been linked to increased mammary cancer. We now propose to determine how heightened GC reactivity disrupts MG development and increases cancer burden by examining the underlying molecular mechanisms connecting glucocorticoid receptor (GR) activation with MG developmental defects (Aim 1).
In Aim 2 we will introduce both pharmacological- and social environmental-interventions in early adulthood to reverse heightened stress reactivity. We predict these interventions will restore normal MG ductal differentiation and thereby decrease later cancer risk.
In Aim 3, we will examine how heightened GC reactivity during puberty inappropriately preserves mammary stem cell (MaSC) populations that are known to increase later cancer risk. We will also investigate the association between circulating steroid hormone levels, in conjunction with their localized production within the MG microenvironment, and ductal maturation and MaSC biology. Completion of these studies will uncover novel stress-mediated molecular and cellular mechanisms of disrupted MG development linked to subsequent mammary cancer and determine whether these stress- mediated events are reversible with early adulthood interventions.
Mammary glands continue to develop throughout late puberty and early adulthood when they are sensitive to environmental disrupters that can increase later breast cancer risk. Using a rat model of human breast development and cancer, our transdisciplinary team, comprised of behavioral, endocrine, and breast cancer biologists, will study how increased stress hormone reactivity, resulting from continuous social isolation, disrupts mammary gland development and stem cell differentiation, thereby increasing the risk of breast cancer. We will also determine if normal mammary gland development can be restored and cancer risk reduced by a pharmacological or social intervention that attenuate stress hormone reactivity.
