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Deleted in Breast Cancer 1 regulates cellular senescence during obesity.

ABSTRACT: Chronic obesity leads to inflammation, tissue dysfunction, and cellular senescence. It was proposed that cellular senescence during obesity and aging drives inflammation and dysfunction. Consistent with this, clearance of senescent cells increases healthspan in progeroid mice. Here, we show that the protein Deleted in Breast Cancer-1 (DBC1) regulates cellular senescence during obesity. Deletion of DBC1 protects preadipocytes against cellular senescence and senescence-driven inflammation. Furthermore, we show protection against cellular senescence in DBC1 KO mice during obesity. Finally, we found that DBC1 participates in the onset of cellular senescence in response to cell damage by mechanism that involves binding and inhibition of HDAC3. We propose that by regulating HDAC3 activity during cellular damage, DBC1 participates in the fate decision that leads to the establishment of cellular senescence and consequently to inflammation and tissue dysfunction during obesity.

SUBMITTER: Escande C

PROVIDER: S-EPMC4172532 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Deleted in Breast Cancer 1 regulates cellular senescence during obesity.

Escande Carlos C Nin Veronica V Pirtskhalava Tamar T Chini Claudia C CC Thereza Barbosa Maria M Mathison Angela A Urrutia Raul R Tchkonia Tamar T Kirkland James L JL Chini Eduardo N EN

Aging cell 20140703 5

Chronic obesity leads to inflammation, tissue dysfunction, and cellular senescence. It was proposed that cellular senescence during obesity and aging drives inflammation and dysfunction. Consistent with this, clearance of senescent cells increases healthspan in progeroid mice. Here, we show that the protein Deleted in Breast Cancer-1 (DBC1) regulates cellular senescence during obesity. Deletion of DBC1 protects preadipocytes against cellular senescence and senescence-driven inflammation. Further ...[more]

PMID: 24992635

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Project description:BackgroundEach year, millions of women undergo breast biopsies. Of these, 80% are negative for malignancy but some may be at elevated risk of invasive breast cancer (IBC) due to the presence of benign breast disease (BBD). Cellular senescence plays a complex but poorly understood role in breast cancer development and the presence or absence of these cells may have prognostic value.MethodsWe conducted a case-control study, nested within a cohort of 15,395 women biopsied for BBD at Kaiser Permanente Northwest between 1971 and 2006. Cases (n = 512) were women who developed a subsequent invasive breast cancer (IBC) at least one year after the BBD biopsy; controls (n = 491) did not develop IBC during the same follow-up period. Using H&E-stained biopsy images, we predicted senescence based on deep learning models trained on replicative senescence (RS), ionizing radiation (IR), and various drug treatments. Age-adjusted and multivariable odds ratios (ORs) and 95% confidence intervals (CI) were estimated using unconditional logistic regression.ResultsThe RS- and IR-derived senescence scores for adipose tissue and the RS-derived score for epithelial tissue were positively associated with the risk of IBC (adipose tissue - RS model: ORq4 vs. q1=1.69, 95% CI 1.03-2.77, and IR model: ORq4 vs. q1=1.73, 95%CI 1.06-2.82; epithelial tissue- RS model: ORq4 vs. q1=1.53, 95% CI 1.05-2.22). The results were stronger among postmenopausal women and women with epithelial hyperplasia with/without atypia, and postmenopausal women also showed a positive association for stromal tissue with the RS model (ORq4 vs. q1=1.84, 95%CI 1.12-3.04). There was an elevated risk of IBC in those with higher senescence scores in both epithelial and adipose tissue compared with those with low senescence scores in both (IR epithelium-IR fat: ORq2-4 vs. q1=2.14, 95% CI 1.30-3.51; and IR epithelium-RS fat: ORq2-4 vs. q1= 2.24, 95% CI 1.15-4.35).ConclusionsThis study suggests that nuclear senescence scores predicted by deep learning models in breast epithelial and adipose tissue can predict the risk of breast cancer development among women with BBD.

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Deleted in Breast Cancer 1 regulates cellular senescence during obesity.

Publications

Deleted in Breast Cancer 1 regulates cellular senescence during obesity.

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