Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.
Genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. The Bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of Myc. Bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly. In this study, we investigated the effects of mammary gland-specific deletion of Bin1 on initiation and progression of breast cancer in mice. Bin1 loss delayed the outgrowth and involution of the glandular ductal network during pregnancy but had no effect on tumor susceptibility. In contrast, in mice where tumors were initiated by the ras-activating carcinogen 7,12-dimethylbenz(a)anthracene, Bin1 loss strongly accentuated the formation of poorly differentiated tumors characterized by increased proliferation, survival, and motility. This effect was specific as Bin1 loss did not accentuate progression of tumors initiated by an overexpressed mouse mammary tumor virus-c-myc transgene, which on its own produced poorly differentiated and aggressive tumors. These findings suggest that Bin1 loss cooperates with ras activation to drive progression, establishing a role for Bin1 as a negative modifier of oncogenicity and progression in breast cancer.
Chang
Mee Young
MY
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
Boulden
Janette
J
Sutanto-Ward
Erika
E
Duhadaway
James B
JB
Soler
Alejandro Peralta
AP
Muller
Alexander J
AJ
Prendergast
George C
GC
D015127:9,10-Dimethyl-1,2-benzanthracene; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D003043:Cocarcinogenesis; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D011905:Genes, ras; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D011247:Pregnancy; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D002273:Carcinogens; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene