Data from Bin1 Ablation Increases Susceptibility to Cancer during Aging, Particularly Lung Cancer

Abstract

<div>Abstract<p>Age is the major risk factor for cancer, but few genetic pathways that modify cancer incidence during aging have been described. <i>Bin1</i> is a prototypic member of the BAR adapter gene family that functions in vesicle dynamics and nuclear processes. <i>Bin1</i> limits oncogenesis and is often attenuated in human cancers, but its role in cancer suppression has yet to be evaluated fully <i>in vivo</i>. In the mouse, homozygous deletion of <i>Bin1</i> 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 <i>Bin1</i> ablation; however, by 18 to 20 months of age, ∼50% of mosaic mice presented with lung adenocarcinoma and ∼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 <i>ras</i>-activating carcinogen, <i>Bin1</i> ablation facilitated progression to more aggressive invasive status. In cases of human lung and colon cancers, immunohistochemical analyses evidenced frequent attenuation of <i>Bin1</i> expression, paralleling observations in other solid tumors. Taken together, our findings highlight an important role for <i>Bin1</i> as a negative modifier of inflammation and cancer susceptibility during aging. [Cancer Res 2007;67(16):7605–12]</p></div>