Document text
Principal Investigator: Matthew J Brady
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $534,283
Funding agency: National Cancer Institute
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.
Terms: <21+ years old><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Attenuated><Behavioral><Biology><Breast><Breast Cancer><Breast Cancer Model><Breast Cancer Prevention><Breast Cancer Risk Factor><Breast Neoplasms><Breast Tumors><Breast tumor model><Cancer Burden><Cancers><Cell Body><Cells><Characteristics><Chronic><Common Rat Strains><Data><Defect><Development><Differentiation and Growth><Duct><Duct (organ) structure><Ductal Cell><Ductal Epithelial Cell><Endocrine Cancer><Endocrine Disrupter><Endocrine Disrupting Chemicals><Endocrine Disruptors><Endocrine Gland Cancer><Endocrine Gland Secretion><Endocrine disrupting agent><Endocrinologist><Environment><Epithelium><Event><Exposure to><Fat Cells><Fatty Tissue><Gene Expression><Gene Transcription><Genetic Transcription><Glucocorticoid Receptor><Glucocorticoids><Goals><Height><Hormones><Human><Impairment><Intervention><Intervention Strategies><Lead><Life><Life Style><Lifestyle><Link><Lipocytes><Malignant Breast Neoplasm><Malignant Endocrine Neoplasm><Malignant Endocrine Tumor><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Duct><Mammary Neoplasms><Mammary gland><Mature Lipocyte><Mature fat cell><Measures><Mediating><Modern Man><Molecular><National Cancer Burden><Pathway interactions><Pb element><Phosphorylation><Physical environment><Population><Population Sizes><Production><Progenitor Cells><Protein Phosphorylation><Psychologic Stress><Psychological Stress><Puberty><RNA Expression><Radiation><Rat><Rats Mammals><Rattus><Receptor Activation><Risk><Risk Factors><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Secondary to><Social Environment><Social isolation><Sprague-Dawley Rats><Stress><Stromal Cells><Structural defect><Structural malformation><Synthetic Estrogens><Testing><Therapeutic Hormone><Therapeutic Steroid Hormone><Transcription><Tumor Burden><Tumor Load><Woman><adipose><adult youth><adulthood><antagonism><antagonist><attenuate><attenuates><breast cancer risk><cancer care><cancer risk><chemical carcinogen><design><designing><developmental><early adulthood><early life exposure><emerging adult><endocrine disrupting compound><environmental intervention><environmental stresses><environmental stressor><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><human model><interdisciplinary collaboration><interventional strategy><life span><lifespan><malignancy><malignant breast tumor><malignant endocrine gland neoplasm><malignant endocrine gland tumor><mammary><mammary cancer model><mammary cancer prevention><mammary gland development><mammary gland morphogenesis><mammary morphogenesis><mammary tumor><mammary tumor model><mammary tumor prevention><model of human><neoplasm/cancer><novel><pathway><pharmacologic><preservation><prevent><prevent breast cancer><preventing><progenitor biology><progenitor cell biology><progenitor cell differentiation><progenitor cell population><progenitor differentiation><progenitor population><receptor expression><response><social><social climate><social context><social interventions><social role><socioenvironment><socioenvironmental><stem and progenitor biology><stem and progenitor cell population><stem and progenitor differentiation><stem cell biology><stem cell differentiation><stem cell population><stem cells><steroid hormone><stress reactivity><stressor><structural abnormalities><structural anomalies><synthetic estrogenic compound><transdisciplinary collaboration><white adipose tissue><xenoestrogen><yellow adipose tissue><young adult><young adulthood>