title: Reduced ING1 levels in breast cancer promotes metastasis.
abstract: INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer.
authors: Department of Biochemistry and Molecular Biology, Calgary, Alberta, CANADA.
authors: Satbir
authors: S
authors: Thakur
authors: Arvind K
authors: AK
authors: Singla
authors: Jie
authors: J
authors: Chen
authors: Uyen
authors: U
authors: Tran
authors: Yang
authors: Y
authors: Yang
authors: Carolina
authors: C
authors: Salazar
authors: Anthony
authors: A
authors: Magliocco
authors: Alexander
authors: A
authors: Klimowicz
authors: Frank
authors: F
authors: Jirik
authors: Department of Biochemistry and Molecular Biology, Calgary, Alberta, CANADA; Oncology University of Calgary, Calgary, Alberta, CANADA.
authors: Karl
authors: K
authors: Riabowol
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011379:Prognosis; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins