Abstract A112: The role of microenvironment in age-related breast cancers

Aside from being a woman, age is the greatest risk factor for developing breast cancer, but there is little understanding how the aging process modifies cancer susceptibility. Multipotent mammary epithelial progenitors are putative roots of some breast cancers, thus expansion combined with increased vulnerability of these cells to transformation could potentiate cancer progression. We have shown in humans that with age, the proportion of multipotent progenitors accumulates, whereas myoepithelial cells decrease, and that these shifts have a basis in altered progenitor function. Progenitors from post-menopausal women gave rise to incompletely differentiated myoepithelial cells and to basal-like luminal cells that expressed markers normally associated with myoepithelial cells in young women. Because epithelial progenitors are thought to be cells-of-origin for a number of breast cancers, and myoepithelial cells are thought to be tumor suppressive, we hypothesize that these tissue-level changes make post-menopausal women more vulnerable to malignant progression. Age-related tissue changes arise in parallel with age-dependent gene expression patterns that have unknown functional consequences and unknown origins. Here we demonstrate that utilizing biomimetic substrata with tuned physical and molecular properties to probe primary human mammary progenitors from women aged 16 to 91 years can reveal age-related functional consequences. As increased breast density is associated with greater breast cancer risk and stiff mechanical microenvironments are known to exacerbate malignant cell behavior, we examined how normal progenitors responded to changes in elastic modulus. Age-related changes in Rho and HIPPO pathway mechano-transduction and transcriptional regulation contributed to accumulation of progenitors by preventing normal differentiation in response to mechanical stimuli. Young progenitors gave rise to more luminal cells on compliant substrata and to more myoepithelial cells on stiffer substrata. However, post-menopausal progenitors were insensitive to physiological mechanical changes and differentiated stochastically instead. To better understand the genesis of the gene expression patterns underlying these age-related functional states, molecular analyses of co-cultures established with primary myoepithelial and luminal epithelial lineages from combinations of young and old individuals were preformed. Age-related gene expression states in luminal cells were imposed through heterotypic cell-cell interactions. Changes in gene expression were coincident with changes in DNA promoter methylation and expression of histone modifying enzymes. We propose that aging results in a continuum of microenvironmental changes that impose epigenetically regulated metastable gene expression states, which are the basis of age-related cell functions that ultimately lead to vulnerable tissue-level phenotypes. Citation Format: Fanny A. Pelissier, Masaru Miyano, James C. Garbe, Martha R. Stampfer, Mark A. LaBarge. The role of microenvironment in age-related breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A112.