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

Sridharan, Deepa M.; Enerio, Shiena; LaBarge, Mark A.; Stampfer, Martha M; Pluth, Janice M.

doi:10.18632/aging.101183

Cited by 2 publications

(6 citation statements)

References 59 publications

(65 reference statements)

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“…We chose to study centrosome aberrations as our surrogate end point of cancer risk, as it has been well documented that aberrations in centrosome number can disrupt tissue architecture and genomic instability; the two main hallmarks of carcinogenesis (Nigg, 2006;Rivera-Rivera & Saavedra, 2016). We and others have also shown that centrosome defects increase with simple and complex damage (Sato et al, 1983;Sudo et al, 2008, Sridharan et al, 2017 and can sensitively differentiate between radiation and age dependent effects (Sridharan et al, 2017). However, the influence of individual genetics in eliciting centrosome defects with exposure to complex damages is not well-understood.…”

Section: Discussionmentioning

confidence: 99%

“…We previously showed that complex damages elicit increased centrosome aberrations in an age dependent manner in HMECs (Sridharan et al, 2017). However, this relationship has not been characterized in HMECs derived from individuals with genetic variations.…”

Section: Increased Centrosome Aberrations In Cells With Genetic Variamentioning

confidence: 96%

“…To compare the effect of p16 silencing, that is sporadically observed as part of malignant progression, the WT 184D strain was compared to its genetically modified post-stasis derivative, wherein p16 was silenced by retroviral transduction of p16 shRNA without introducing gross genomic errors (Garbe et al, 2014). A subset of six primary WT HMEC strains chosen from a wider cohort of individuals of different ages that were used in our previous study (Sridharan et al, 2017), were used to examine the impact of radiation quality on age dependent genomic instability. These included two pre-stasis strains chosen from individuals in three distinct age groups: (young: specimen 48R (16y) and 240 L (19y); middle-age: specimen 60R (47y) and 030 (49y) and old: specimen 71C (65y) and specimen 122 L (66y).…”

Section: Cell Strainsmentioning

confidence: 99%

“…The beam diameter was 20 × 20 cm 2 square, with a uniform center and variation of+/− 10% at the periphery. Cells were exposed to either a low dose of 0.05 Gy or high dose of 0.5 Gy chosen based on effectiveness of this dose in generating centrosome aberrations as shown previously (Sridharan et al, 2017). Dosimetry calibration at NSRL was carried out using standardized techniques outlined in the NSRL user guide (https://www.bnl.gov/nsrl/ userguide/dosimetry-calibration.php).…”

Section: Irradiationmentioning

confidence: 99%

“…As radiation quality effects were difficult to discern when comparing genetic variants, we attempted to tease out the difference in effectiveness of Si 93 MeV/u and Ti 300 MeV/u using a subset of the aged cohort of cell strains (2 young, 2 middle aged and 2 older strains) previously shown to exhibit an age effect with high dose Ti 300 MeV/u exposure (Sridharan et al, 2017). Centrosome aberrations were assessed 9 days post exposure.…”

Section: Validating the Linear Relationship Between Age And Centrosommentioning

confidence: 99%

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Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure

Sridharan

Enerio

Wang

et al. 2019

Life Sciences in Space Research

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There exists a wide degree of genetic variation within the normal human population which includes disease free individuals with heterozygote defects in major DNA repair genes. A lack of understanding of how this genetic variation impacts cellular phenotypes that inform cancer risk post heavy ion exposure poses a major limitation in developing personalized cancer risk assessment astronauts. We initiated a pilot study with Human Mammary Epithelial Cell strains (HMEC) derived from wild type, a p16 silenced derivative of wild type, and various genetic variants that were heterozygote for DNA repair genes; BRCA1, BRCA2 and ATM. Cells strains were exposed to different high and low LET radiation qualities to generate both simple and complex lesions and centrosome aberrations were examined as a surrogate marker of genomic instability and cancer susceptibility post different exposures. Our results indicate that centrosome aberration frequency is higher in the genetic variants under study. The aberration frequency increases with dose, complexity of the lesion generated by different radiation qualities and age of the individual. This increase in genomic instability correlates with elevated checkpoint activation post radiation exposure. These studies suggest that the influence of individual genetics on cell cycle regulation could modify the degree of early genomic instability in response to complex lesions and potentially define cancer predisposition in response to HZE exposure. These results will have significant implications in estimating cancer susceptibility in genetically variant individuals exposed to HZE particles.

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Section: Discussionmentioning

confidence: 99%

Section: Increased Centrosome Aberrations In Cells With Genetic Variamentioning

confidence: 96%

Section: Cell Strainsmentioning

confidence: 99%

Section: Irradiationmentioning

confidence: 99%

Section: Validating the Linear Relationship Between Age And Centrosommentioning

confidence: 99%

See 3 more Smart Citations

Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure

Sridharan

Enerio

Wang

et al. 2019

Life Sciences in Space Research

Self Cite

View full text Add to dashboard Buy / Rent full text

show abstract

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

Cited by 2 publications

References 59 publications

Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure

Genetic variation and radiation quality impact cancer promoting cellular phenotypes in response to HZE exposure

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