title: Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells.
abstract: Exposures to various DNA damaging agents can deregulate a wide array of critical mechanisms that maintain genome integrity. It is unclear how these processes are impacted by one's age at the time of exposure and the complexity of the DNA lesion. To clarify this, we employed radiation as a tool to generate simple and complex lesions in normal primary human mammary epithelial cells derived from women of various ages. We hypothesized that genomic instability in the progeny of older cells exposed to complex damages will be exacerbated by age-associated deterioration in function and accentuate age-related cancer predisposition. Centrosome aberrations and changes in stem cell numbers were examined to assess cancer susceptibility. Our data show that the frequency of centrosome aberrations proportionately increases with age following complex damage causing exposures. However, a dose-dependent increase in stem cell numbers was independent of both age and the nature of the insult. Phospho-protein signatures provide mechanistic clues to signaling networks implicated in these effects. Together these studies suggest that complex damage can threaten the genome stability of the stem cell population in older people. Propagation of this instability is subject to influence by the microenvironment and will ultimately define cancer risk in the older population.
authors.affiliation: Division of Biological Systems and Engineering, Department of Organismal Systems and Bioresilience, Lawrence Berkeley National Laboratory, Berkeley, CA 94803, USA.
authors.forename: Deepa M
authors.initials: DM
authors.lastname: Sridharan
authors.affiliation: Division of Biological Systems and Engineering, Department of Organismal Systems and Bioresilience, Lawrence Berkeley National Laboratory, Berkeley, CA 94803, USA.
authors.forename: Shiena
authors.initials: S
authors.lastname: Enerio
authors.affiliation: Department of Population Sciences, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: LaBarge
authors.affiliation: Division of Biological Systems and Engineering, Department of Organismal Systems and Bioresilience, Lawrence Berkeley National Laboratory, Berkeley, CA 94803, USA.
authors.forename: Martha M
authors.initials: MM
authors.lastname: Stampfer
authors.affiliation: Division of Biological Systems and Engineering, Department of Organismal Systems and Bioresilience, Lawrence Berkeley National Laboratory, Berkeley, CA 94803, USA.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Pluth
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D002478:Cells, Cultured; D018385:Centrosome / Q000528:radiation effects*; D004249:DNA Damage / Q000528:radiation effects; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008875:Middle Aged; D013234:Stem Cells / Q000502:physiology / Q000528:radiation effects*
keywords: age of exposure; breast cancer susceptibility; centrosome aberrations; complex lesions; genome instability; stem cells