title: Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer.
abstract: Inhibitor of growth 4 (ING4) is a candidate tumor suppressor gene that was shown to be deleted in 10% to 20% of breast cancers by array comparative genome hybridization analysis. We developed fluorescent in situ hybridization to detect the ING4 gene directly in the tissue samples on tumor tissue microarrays. We evaluated the ING4 gene status in 1033 breast cancer tissue samples and observed that ING4 was deleted in 16.5% (170/1033) of all breast cancers. ING4 deletion was significantly associated with Her2 overexpression: of the tumors with ING4 deletion, 23.8% (39/164) were human epidermal growth factor 2 (HER2) positive, as compared with 14.1% (115/814) of the tumors without ING4 deletion (P = .002). In addition, the tumors with ING4 deletion were more likely to belong to the HER2 molecular subtype (estrogen receptor negative/progesterone receptor negative/human epidermal growth factor positive) of breast cancer, compared with the other subtypes (28.4% HER2 versus 15.7% all, P = .002). ING4 deletion did not affect survival outcome of all patients with breast cancer (P = .797) or of the patients with HER2-positive tumors (P = .792). We conclude that ING4 deletion in breast cancer is relatively common, as 1 in 6 breast cancer harbors ING4 deletion. Furthermore, ING4 deletion is more prevalent in HER2-positive tumors, suggesting a functional antagonistic relationship between the ING4 tumor suppressor and the HER2 oncogene. These results sustain the view that ING4 is a tumor suppressor in breast cancer and suggest that ING4 deletion may contribute to the pathogenesis of HER2-positive breast cancer.
authors.affiliation: Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4103 Basel, Switzerland. ctapia@uhbs.ch
authors.forename: Coya
authors.initials: C
authors.lastname: Tapia
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
authors.forename: Sandra
authors.initials: S
authors.lastname: Schneider
authors.forename: Ergin
authors.initials: E
authors.lastname: Kilic
authors.forename: Uwe
authors.initials: U
authors.lastname: Güth
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.forename: Suwon
authors.initials: S
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D018797:Cell Cycle Proteins / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D025521:Tumor Suppressor Proteins; C483230:ING4 protein, human; C508053:ERBB2 protein, human