Loss of heterozygosity in ING3 and ING5 genes in breast cancer

The tumor suppressor genes (TSGs) ING3 and ING5, members of the inhibitor of growth gene family, are effective in inhibition of cell growth and induction of apoptosis. However, in many cancer types, one of the alleles of a TSG is lost through carcinogenesis, while the remaining allele is usually inactivated through a process called loss of heterozygosity (LOH). Previous studies in head and neck cancer revealed that allelic loss and reduced expression is a common pattern of ING gene family members. Fifty paraffin-embedded breast cancer tissues were analyzed by polymerase chain reaction and denatured-polyacrylamide gel electrophoresis for LOH status. The allelic deletion frequency of ING3 and ING5 were detected as 14% and 17% in breast cancer patients, respectively. No significant relationship was detected between ING3 LOH status and clinicopathological variables. Our data also suggest that both ING3 and ING5 LOH statuses have no significant effect in overall survival and disease-free survival of breast cancer patients. These results provide a rational explanation and relative contribution for the complexity of tumor formation, whereby allelic loss of ING3 and ING5 genes is not a major factor for breast cancer but is rather a part of a larger complex mechanism.

Loss of heterozygosity in ING3 and ING5 genes in breast cancer

The tumor suppressor genes (TSGs) ING3 and ING5, members of the inhibitor of growth gene family, are effective in inhibition of cell growth and induction of apoptosis. However, in many cancer types, one of the alleles of a TSG is lost through carcinogenesis, while the remaining allele is usually inactivated through a process called loss of heterozygosity (LOH). Previous studies in head and neck cancer revealed that allelic loss and reduced expression is a common pattern of ING gene family members. Fifty paraffin-embedded breast cancer tissues were analyzed by polymerase chain reaction and denatured-polyacrylamide gel electrophoresis for LOH status. The allelic deletion frequency of ING3 and ING5 were detected as 14% and 17% in breast cancer patients, respectively. No significant relationship was detected between ING3 LOH status and clinicopathological variables. Our data also suggest that both ING3 and ING5 LOH statuses have no significant effect in overall survival and disease-free survival of breast cancer patients. These results provide a rational explanation and relative contribution for the complexity of tumor formation, whereby allelic loss of ING3 and ING5 genes is not a major factor for breast cancer but is rather a part of a larger complex mechanism.

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  • Aguissa-Toure AH, Wong RP, Li G (2011). The ING family tumor suppressors: from structure to function. Cell Mol Life Sci 68: 45–54.
  • American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA, USA: American Cancer Society, 2013.
  • Andersson I, Janzon L (1997). Reduced breast cancer mortality in women under age 50: updated results from the Malmo Mammographic Screening Program. J Natl Cancer Inst Monogr 63–67.
  • Bassam BJ, Gresshoff PM (2007). Silver staining DNA in polyacrylamide gels. Nat Protoc 2: 2649–2654.
  • Borkosky SS, Gündüz M, Beder L, Tsujigiwa H, Tamamura R, Gündüz E, Katase N, Rodriguez AP, Sasaki A, Nagai N et al. (2010). Allelic loss of the ING gene family loci is a frequent event in ameloblastoma. Oncol Res 18: 509–518.
  • Campos EI, Chin MY, Kuo WH, Li G (2004). Biological functions of the ING family tumor suppressors. Cellular and Molecular Life Sciences 61: 2597–2613.
  • Cengiz B, Gündüz E, Gündüz M, Beder LB, Tamamura R, Bagci C, Yamanaka N, Shimizu K, Nagatsuka H (2010). Tumor- specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma. Int J Cancer 127: 2088–2094.
  • Cengiz B, Gündüz M, Nagatsuka H, Beder L, Gündüz E, Tamamura R, Mahmut N, Fukushima K, Ali MA, Naomoto Y et al. (2007). Fine deletion mapping of chromosome 2q21-37 shows three preferentially deleted regions in oral cancer. Oral Oncol 43: 241–247.
  • Coles AH, Jones SN (2009). The ING gene family in the regulation of cell growth and tumorigenesis. J Cell Physiol 218: 45–57.
  • Garkavtsev I, Kazarov A, Gudkov A, Riabowol K (1996). Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. Nat Genet 14: 415–420.
  • Gong W, Suzuki K, Russell M, Riabowol K (2005). Function of the ING family of PHD proteins in cancer. Int J Biochem Cell Biol 37:1054–1065.
  • Gündüz M, Beder LB, Gündüz E, Nagatsuka H, Fukushima K, Pehlivan D, Cetin E, Yamanaka N, Nishizaki K, Shimizu K et al. (2008). Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer. Cancer Sci 99: 531– 538.
  • Gündüz M, Demircan K, Gündüz E, Katase N, Tamamura R, Nagatsuka, H (2009). Potential usage of ING family members in cancer diagnostics and molecular therapy. Curr Drug Targets 10: 465–476.
  • Gündüz M, Gündüz E, Rivera RS, Nagatsuka H (2008). The inhibitor of growth (ING) gene family: potential role in cancer therapy. Curr Cancer Drug Targets 8: 275–284.
  • Gündüz M, Ouchida M, Fukushima K, Hanafusa H, Etani T, Nishioka S, Nishizaki K, Shimizu K (2000). Genomic structure of the human ING1 gene and tumor-specific mutations detected in head and neck squamous cell carcinomas. Cancer Res 60: 3143–3146.
  • Gündüz M, Ouchida M, Fukushima K, Ito S, Jitsumori Y, Nakashima T, Nagai N, Nishizaki K, Shimizu K (2002). Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers. Oncogene 21: 4462–4470.
  • Knudson AG Jr (1971). Mutation and cancer: statistical study of retinoblastoma. P Natl Acad Sci USA 68: 820–823.
  • Li X, Nishida T, Noguchi A, Zheng Y, Takahashi H, Yang X, Masuda S, Takano Y (2010). Decreased nuclear expression and increased cytoplasmic expression of ING5 may be linked to tumorigenesis and progression in human head and neck squamous cell carcinoma. J Cancer Res Clin Oncol 136: 1573–1583.
  • Mendes-Pereira AM, Sims D, Dexter T, Fenwick K, Assiotis I, Kozarewa I, Mitsopoulos C, Hakas J, Zvelebil M, Lord CJ et al. (2012). Genome- wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. P Natl Acad Sci USA 109: 2730–2735.
  • Nagashima M, Shiseki M, Pedeux RM, Okamura S, Kitahama-Shiseki M, Miura K, Yokota J, Harris CC (2003). A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis. Oncogene 22: 343–350.
  • Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S, Onogi H, Higashimoto Y, Appella E, Yokota J et al. (2003). p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res 63: 2373–2378.
  • Shridhar V, Sun QC, Miller OJ, Kalemkerian GP, Petros J, Smith DI (1997). Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal cell carcinomas. Oncogene 15: 2727–2733.
  • Soliman MA, Riabowol K (2007). After a decade of study-ING, a PHD for a versatile family of proteins. Trends Biochem Sci 32: 509–519.
  • Unoki M, Kumamoto K, Robles AI, Shen JC, Zheng ZM, Harris CC (2008). A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis. FEBS Lett 582: 3868–3874.
  • Wang Y, Li G (2006). ING3 promotes UV-induced apoptosis via Fas/ caspase-8 pathway in melanoma cells. J Biol Chem 281: 11887– 11893.
  • Xing YN, Yang X, Xu XY, Zheng Y, Xu HM, Takano Y, Zheng HC (2011). The altered expression of ING5 protein is involved in gastric carcinogenesis and subsequent progression. Hum Pathol 42: 25–35.
  • Zhang F, Baumer N, Rode M, Ji P, Zhang T, Berdel WE, Muller-Tidow C (2011). The inhibitor of growth protein 5 (ING5) depends on INCA1 as a co-factor for its antiproliferative effects. PLoS One 6: e21505.
  • Zheng HC, Xia P, Xu XY, Takahashi H, Takano Y (2011). The nuclear to cytoplasmic shift of ING5 protein during colorectal carcinogenesis with their distinct links to pathologic behaviors of carcinomas. Hum Pathol 42: 424–433.
Turkish Journal of Biology-Cover
  • ISSN: 1300-0152
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Loss of heterozygosity in ING3 and ING5 genes in breast cancer

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