title: Aging is associated with an expansion of CD49fhimammary stem cells that show a decline in function and increased transformation potential.
abstract: Breast cancer incidence increases during aging, yet the mechanism of age-associated mammary tumorigenesis is unclear. Mammary stem cells are believed to play an important role in breast tumorigenesis, but how their function changes with age is unknown. We compared mammary epithelial cells isolated from young and old mammary glands of different cohorts of C57BL6/J and BALB/c mice, and our findings revealed that old mammary glands were characterized by increased basal cell pool comprised of mostly CD49fhicells, altered luminal-to-basal cell ratio, and irregular ductal morphology. More interestingly, basal stem cells in old mice were increased in frequency, but showed a functional decline of differentiation and increased neoplastic transformation potential. Gene signature enrichment analysis revealed a significant enrichment of a luminal cell gene expression signature in the basal stem cell-enriched population from old mice, suggesting some luminal cells were expressing basal markers. Immunofluorescence staining confirmed the presence of luminal cells with high CD49f expression in hyperplastic lesions implicating these cells as undergoing luminal to basal phenotypic changes during aging. Whole transcriptome analysis showed elevated immune and inflammatory responses in old basal stem cells and stromal cells, which may be the underlying cause for increased CD49fhibasal-like cells in aged glands.
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|School of Laboratory Medicine and Life Science, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Qiaoxiang
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|School of Laboratory Medicine and Life Science, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Yuanshuo
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Fuchuang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gu
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Anqi
authors.initials: A
authors.lastname: Wu
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Danhan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Pathology, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.affiliation: Flow Cytometry Facility, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Daniel
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Vivienne L
authors.initials: VL
authors.lastname: Rebel
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Christi A
authors.initials: CA
authors.lastname: Walter
authors.affiliation: School of Laboratory Medicine and Life Science, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.affiliation: Institute of Environmental Safety and Human Health, Wenzhou Medical University, University Town, Wenzhou 325035, China.
authors.forename: Changjiang
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, San Antonio, TX 78299, USA.|Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX 78299, USA.
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D039503:Integrin alpha6 / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology*; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D039503:Integrin alpha6
keywords: aging; breast cancer; mammary stem cell; neoplasia