Aging alters transcriptional circuitries and SLUG-mediated cellular states of mouse mammary epithelium.
Gross, Kayla.
2019
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Age-associated decline
in stem cell function predisposes tissues to dysfunction and disease and is driven by
disruption of cellular homeostasis. The bulk of age-associated changes to the mammary
epithelial epithelium and its stem/progenitor compartments have been studied after the
onset of reproductive senescence (menopause) that occurs around midlife, yet nearly half
of women in the U.S. are ... read morediagnosed with breast cancer before age 62, suggesting that
age-associated risk factors for breast cancer development are already present before or
after midlife. As such, we sought to investigate the consequences of perimenopausal
transition on mammary tissue and stem cell biology. Here we show that middle-aged,
perimenopausal mice exhibit facultative stem cell decline, aberrant luminal
differentiation in basal cells, and increased genomic and protein stress. Additionally,
we demonstrate that young adult mice lacking the transcription factor SLUG/SNAI2 exhibit
many of the molecular and cellular features of perimenopause, including facultative stem
cell decline, aberrant luminal differentiation in basal cells, and increased DNA damage.
Collectively, these results show that the transition to menopause triggers cellular
stress that leads to stem cell decline, which is phenocopied by SLUG loss. These
findings also link a transcription factor that controls stem cell activity and cell
identity to DNA repair and aging.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisor: Charlotte Kuperwasser.
Committee: Karl Munger, James Schwob, and Lidija Covic.
Keyword: Cellular biology.read less - ID:
- 2801pv45q
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