The association of aging with increased incidence of breast cancer is well known, but little understood. Emphasis has been placed on differences among tumors as a function of age, while considerably less attention is given to changes that occur normally in mammary epithelium during the process of aging, which may facilitate tumorigenesis. A commonly invoked mechanism to help explain age-related cancer is the gradual accumulation of mutations and epigenetic changes. However, it is known that cells harboring even the strongest oncogenes can appear phenotypically normal when held in check by normal tissue architecture. Most tissues exhibit functional and regenerative decline with advancing age. Our over-arching hypothesis is that age-associated breast cancer may partly result from loss-of-function alterations, e.g. changes to structural and architectural gatekeepers that maintain normal tissue organization and polarity, which leads to deleterious imbalances of or changes in the activity of progenitors and more differentiated epithelial lineages. That the majority of women live healthy cancer-free lives suggests age-related changes to the breast tissue are usually benign, but in cases when deleterious genomic changes also are present the combination with deteriorating microenvironments may be catastrophic. Some age-associated changes in breast includes increased fat and estrogen receptor expression;decreased connective tissue, numbers of alveoli and overall breast density;changes in collagen-type expression, and discontinuities in the basement membrane of the mammary gland. We simply do not know what impact these changes have on epithelial cell biology or on the architecture and organization with the gland. This proposal will use the Human Mammary Epithelial Cell (HMEC) Aging Resource, which is a large collection of normal finite-life span HMEC strains that were established from patients ranging in age from 16-91, to perform heretofore impossible quantitative and functional analysis of normal HMEC as a function of age. Changes in populations and functional properties of stem, progenitor, and more differentiated lineages will be measured, as will the ability of HMEC to form and maintain a normal organized bilayered architecture, an ability that is lost early in tumorigenesis, is affected by the aging process. In parallel with our functional analysis, we will perform an automated quantitative analysis of over 500 histological sections of normal breast to generate an atlas of aging-associated changes in the breast tissue, and to identify changes in organization in vivo among the different HMEC lineages. Our goal is to identify potentially deleterious changes that occur in most women during the aging process that could be targets of future prophylactic and preventative strategies.

Public Health Relevance

It has been known for decades that aging is one of the principle risk factors for breast cancer, yet the impact of the normal aging process on function and architecture of normal breast epithelium is not well characterized. This proposal uses unique biological and technological assets that were developed at the Lawrence Berkeley National Laboratory to generate a previously unrealizable atlas of functional and architectural changes that occur during the process of aging. We will identify normal age-associated changes that may create a predisposition towards malignant states when combined with additional genetic mutations, with a goal of informing future prophylactic or preventative strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040081-04
Application #
8732598
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Kohanski, Ronald A
Project Start
2011-09-30
Project End
2016-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$406,935
Indirect Cost
$181,935
Name
Lawrence Berkeley National Laboratory
Department
Biology
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Pelissier, Fanny A; Garbe, James C; Ananthanarayanan, Badriprasad et al. (2014) Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors. Cell Rep 7:1926-39
Labarge, Mark A; Parvin, Bahram; Lorens, James B (2014) Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics. Adv Drug Deliv Rev 69-70:123-31
Sputova, Klara; Garbe, James C; Pelissier, Fanny A et al. (2013) Aging phenotypes in cultured normal human mammary epithelial cells are correlated with decreased telomerase activity independent of telomere length. Genome Integr 4:4
Labarge, Mark A; Garbe, James C; Stampfer, Martha R (2013) Processing of human reduction mammoplasty and mastectomy tissues for cell culture. J Vis Exp :
LaBarge, Mark A (2012) On stem cells in the human breast. Cold Spring Harb Perspect Biol 4:
Garbe, James C; Pepin, Francois; Pelissier, Fanny A et al. (2012) Accumulation of multipotent progenitors with a basal differentiation bias during aging of human mammary epithelia. Cancer Res 72:3687-701