Effects of chronic pubertal stressors on mammary gland biology and cancer risk

PROJECT ABSTRACT
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.

Grant Number: 5R01CA239719-06
NIH Institute/Center: NIH
Principal Investigator: Matthew Brady