Abstract 914: Age-associated neoplastic transformation of mammary stem cells

Abstract

Abstract Incidence rate of breast cancer increases significantly with age. However, the mechanism of age-associated mammary tumorigenesis is unknown. Although mammary stem/progenitor cells have been proposed as the cells of origin for breast cancer, the mechanism remains largely elusive. Previously we discovered that in the old (28 to 30 month-old) mouse mammary gland, the luminal cells in the hyperplastic lesions elevated expression of CD49f, which is a basal cell marker. This led to an increased percentage of mammary stem cells (MaSCs) marked by CD49fhi in the old in comparison to the young (3 to 6 month-old). Similarly, old (>60 yr) human mammary ducts in the adjacent normal tissues from patients with breast cancer showed more hyperplastic lesions and CD49fhi luminal cells than young (<40 yr) tissues. Regenerated mammary glands by the old CD49fhi MaSCs through in vivo transplantation in cleared mammary fat pads showed more hyperplastic and dysplastic lesions than those regenerated by the young CD49fhi MaSCs, suggesting the old CD49fhi MaSCs contain transformed MaSCs. Moreover, gene set enrichment analysis of whole genome transcriptome data showed that they also have elevated expression of luminal cell specific genes and reduced expression of basal cell specific genes. Through large scale screening with flow cytometry guided by bioinformatics analysis, we found that Lin- CD24med CD49fhi CD13+ CD73- mammary epithelial cells had increased number of MaSCs. By comparing young (3 to 6 months old) and old Balb/C mice, we found that the frequency of this specific MaSCs was significantly increased by four folds in old mammary epithelial cells (young: 4%, old: 16%). In contrast, relative percentage of Lin- CD24med CD49fhi CD13- CD73+ cells significantly decreased (young: 46%, old: 16%) during aging while the CD13 and CD73 double positive or double negative subpopulations remained unchanged. CD13+ CD73- cells generated significantly many more mammospheres (around 40 spheres per 1,000 cells) in suspension culture than other three types of cells (around 2 spheres per 1,000 cells). However, there was no significant difference between the young and old in terms of sphere formation efficiency for any of the four subpopulations marked by CD13 and CD73. We are studying whether anyone of these four subpopulation from CD49fhi old cells will generate more hyperplastic and dysplastic lesions in regenerated glands than the other subpopulations as well as than the corresponding young subpopulation. Our study show that CD13 and CD73 may be the markers for the identification of tumor-initiating MaSCs. Citation Format: Xiang Gu, Hakim Bouamar, Kyle Pressley, LuZhe Sun. Age-associated neoplastic transformation of mammary stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 914. doi:10.1158/1538-7445.AM2017-914