Abstract
Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. Bin1 is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. Bin1 limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully in vivo. In the mouse, homozygous deletion of Bin1 causes developmental lethality, so to assess this role, we examined cancer incidence in mosaic null mice generated by a modified Cre-lox technology. During study of these animals, one notable phenotype was an extended period of female fecundity during aging, with mosaic null animals retaining reproductive capability until the age of 17.3 +/- 1.1 months. Through 1 year of age, cancer incidence was unaffected by Bin1 ablation; however, by 18 to 20 months of age, approximately 50% of mosaic mice presented with lung adenocarcinoma and approximately 10% with hepatocarcinoma. Aging mosaic mice also displayed a higher incidence of inflammation and/or premalignant lesions, especially in the heart and prostate. In mice where colon tumors were initiated by a ras-activating carcinogen, Bin1 ablation facilitated progression to more aggressive invasive status. In cases of human lung and colon cancers, immunohistochemical analyses evidenced frequent attenuation of Bin1 expression, paralleling observations in other solid tumors. Taken together, our findings highlight an important role for Bin1 as a negative modifier of inflammation and cancer susceptibility during aging.
Highlights
Aging is the major risk factor for cancer
Homozygous deletion of Bin1 in mice causes perinatal lethality associated with a severe hypertrophic cardiomyopathy [21]
EIIa-Cre and Bin1KO/+ mice were interbred to obtain Bin1KO/+;EIIa-Cre(+/+) offspring. These offspring were crossed with Bin1flox/flox mice to obtain Bin1KO/floxD;EIIa-Cre(+/À) mice (Bin1 mosaic nulls), Bin1+/ floxD;EIIa-Cre(+/À) mice (Bin1 mosaic heterozygotes), and Bin1+/ flox;EIIa-Cre(+/À) mice (Bin1 non-recombined controls)
Summary
Aging is the major risk factor for cancer. Most preclinical models of cancer employ young animals that are unlikely to fully recapitulate the participation of the inflammatory tissue microenvironment, immune senescence, or other ageassociated factors. Insights into the cause and treatment of cancer might benefit from studies of genetic pathways that modify cancer incidence during aging. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Wang: Cancer Center, Tongji University Affiliated Shanghai East Hospital, Shanghai, P.R. China. Current address for A.P. Soler: Richfield Laboratory of Dermatopathology, Cincinnati, OH
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