Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer.
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.
Chang
Mee Young
MY
Lankenau Institute for Medical Research, Lankenau Hospital, Wynnewood, Pennsylvania 19096, USA.
Boulden
Janette
J
Katz
Jessica B
JB
Wang
Liwei
L
Meyer
Thomas J
TJ
Soler
Alejandro Peralta
AP
Muller
Alexander J
AJ
Prendergast
George C
GC
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins