A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis.
ING4 is a candidate tumor suppressor gene that is deleted in 10% to 20% of human breast cancers and is mutated in various human cancer cell lines. To evaluate whether ING4 has a tumor-suppressive role in breast tissue, we overexpressed it in mouse mammary glands using a transplant system. Ectopic expression of ING4 suppressed MYC-induced mammary hyperplasia, but not tumorigenesis. In the same model system, we show that a COOH-terminal truncation mutant of ING4 found in human cancer cells could act alone to induce abnormal gland structures resembling mammary hyperplasia, which did not progress to tumors. However, coexpression of the ING4 mutant with MYC increased the penetrance and metastasis of MYC-initiated mammary tumors, giving rise to tumors with more organized acinar structures. Similarly, in vitro expression of the ING4 mutant in MCF10A mammary epithelial cells reinforced tight junctional structures. Our results provide direct functional evidence that ING4 could suppress the early stages of breast cancer and that dominant mutant alleles of ING4 might contribute to malignant development.
Kim
Suwon
S
G.W. Hooper Research Foundation, University of California, San Francisco, California, USA. Suwon@email.arizona.edu
Welm
Alana L
AL
Bishop
J Michael
JM
D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins