Karyotypic Instability and Centrosome Aberrations in the Progeny of Finite Life-Span Human Mammary Epithelial Cells Exposed to Sparsely or Densely Ionizing Radiation

Sudo, Hiroko; Garbe, James C.; Stampfer, Martha R.; Barcellos‐Hoff, Mary Helen; Kronenberg, Amy

doi:10.1667/rr1317.1

Cited by 27 publications

(17 citation statements)

References 60 publications

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“…High dose exposures significantly increase the aberration frequency for both types of radiation. These results are in line with previous data that have shown a dose-dependent increase in centrosome aberrations with exposure to simple and complex damages [25, 26]. However, a linear relationship between the frequency of radiation-induced centrosome aberrations with age of the exposed cell strain was exclusively noted only with exposures to a radiation type that caused complex damages.…”

Section: Discussionsupporting

confidence: 92%

Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells

Sridharan

Enerio

LaBarge

et al. 2017

Aging

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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.

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Section: Discussionsupporting

confidence: 92%

Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells

Sridharan

Enerio

LaBarge

et al. 2017

Aging

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“…This observation raises the question of whether these events occur at a single point in time as a direct result of exposure or evolve over time after exposure in the tissue environment. The latter possibility is consistent with radiation-induced genomic instability [40–42]. The former possibility of numerous changes occurring simultaneously from a single event is consistent with the hypothesis that cancers evolve rapidly in bursts of multiple genetic changes [43].…”

Section: Discussionsupporting

confidence: 73%

Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change

et al. 2017

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Exposure to a small number of high-energy heavy charged particles (HZE ions), as found in the deep space environment, could significantly affect astronaut health following prolonged periods of space travel if these ions induce mutations and related cancers. In this study, we used an in vivo mutagenesis assay to define the mutagenic effects of accelerated 56Fe ions (1 GeV/amu, 151 keV/μm) in the mouse kidney epithelium exposed to doses ranging from 0.25 to 2.0 Gy. These doses represent fluences ranging from 1 to 8 particle traversals per cell nucleus. The Aprt locus, located on chromosome 8, was used to select induced and spontaneous mutants. To fully define the mutagenic effects, we used multiple endpoints including mutant frequencies, mutation spectrum for chromosome 8, translocations involving chromosome 8, and mutations affecting non-selected chromosomes. The results demonstrate mutagenic effects that often affect multiple chromosomes for all Fe ion doses tested. For comparison with the most abundant sparsely ionizing particle found in space, we also examined the mutagenic effects of high-energy protons (1 GeV, 0.24 keV/μm) at 0.5 and 1.0 Gy. Similar doses of protons were not as mutagenic as Fe ions for many assays, though genomic effects were detected in Aprt mutants at these doses. Considered as a whole, the data demonstrate that Fe ions are highly mutagenic at the low doses and fluences of relevance to human spaceflight, and that cells with considerable genomic mutations are readily induced by these exposures and persist in the kidney epithelium. The level of genomic change produced by low fluence exposure to heavy ions is reminiscent of the extensive rearrangements seen in tumor genomes suggesting a potential initiation step in radiation carcinogenesis.

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“…IR acts more like a switch in priming cells to undergo EMT in that irradiation with either 2 or 200 cGy seem to be equally effective. 1 Likewise, there does not seem to be dose-dependent induction of RIGI (7). Perhaps more importantly, although cells irradiated with 10 cGy exhibited CA, CA and DDR foci in cells cloned after 10 cGy were comparable with controls, suggesting that there is a threshold.…”

Section: Discussionmentioning

confidence: 91%

“…We have recently shown RIGI in clonally expanded, finite life span, normal human mammary epithelial cells (HMEC) as measured by aberrant karyotypes and supernumery centrosomes (7). Centrosome aberrations (CA) can induce variable mitotic outcomes including aneuploidy, genomic instability, and cell death (12).…”

Section: Introductionmentioning

confidence: 99%

Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability

et al. 2008

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Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. We investigated the mechanism of this nontargeted effect in human mammary epithelial cells (HMEC) exposed to low doses of radiation. We identified a centrosome-associated expression signature in irradiated HMEC and show here that centrosome deregulation occurs in the first cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically unstable as evidenced by spontaneous DNA damage, tetraploidy, and aneuploidy. Clonal analysis of genomic instability showed a threshold of >10 cGy. Treatment with transforming growth factor B1 (TGFB), which is implicated in regulation of genomic stability and is activated by radiation, reduced both the centrosome expression signature and centrosome aberrations in irradiated HMEC. Furthermore, TGFB inhibition significantly increased centrosome aberration frequency, tetraploidy, and aneuploidy in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome aberrations, TGFB selectively deleted unstable cells via p53-dependent apoptosis. Together, these studies show that radiation deregulates centrosome stability, which underlies genomic instability in normal human epithelial cells, and that this can be opposed by radiation-induced TGFB signaling.

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Karyotypic Instability and Centrosome Aberrations in the Progeny of Finite Life-Span Human Mammary Epithelial Cells Exposed to Sparsely or Densely Ionizing Radiation

Cited by 27 publications

References 60 publications

Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells

Lesion complexity drives age related cancer susceptibility in human mammary epithelial cells

Simulated space radiation-induced mutants in the mouse kidney display widespread genomic change

Targeted and Nontargeted Effects of Ionizing Radiation That Impact Genomic Instability

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