Hani ALOTAİBİ, Esra BAĞRIYANIK ERDAL, Emine KANDEMİŞ, İmge KUNTER, Tülay CANDA

Alteration in the subcellular location of the inhibitor of growth protein p33(ING1b) in estrogen receptor alpha positive breast carcinoma cells

ING1 has regulatory roles in the expression of genes associated with proliferation, apoptosis, and senescence. p33(ING1b) is the most widely expressed isoform of the gene. Downregulation of its nuclear expression is involved in differentiation and pathogenesis in invasive breast carcinoma. Yet the mechanism(s) by which p33 nuclear targeting is regulated remains unknown. In this study, we analyzed human invasive breast carcinoma tissue samples by immunostaining with p33 and correlating p33 location with the presence of ERα. Our findings show the expression of p33 protein in ERα-positive tumor samples was in the nucleus alone, while the expression was mainly in the cytoplasm in ERα-negative tumor samples. Examination of the localization of p33 in the nucleus and/or cytoplasm in several different cell lines demonstrated 17β-estradiol (E2) treatment causes dramatic compartmental shift in p33 protein from the cytoplasm to the nucleus in ERα-positive MDA-66 cells. No significant differences in ERα-negative MDA-MB-231 cells in the same conditions were observed. We show for the first time nuclear localization of p33 is regulated by estradiol induction in ERα-positive breast cancer cells. These results suggest compartmental shift in p33 by ER signaling may be an important molecular event in the differentiation and pathogenesis of invasive breast cancer.

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Alotaibi H, Yaman EÇ, Demirpençe E, Tazebay UH (2006). Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I- symporter gene. Biochem Biophys Res Commun 345: 1487-1496.
Bianco NR, Perry G, Smith MA, Templeton DJ, Montano MM (2003). Functional implications of antiestrogen induction of quinone reductase: inhibition of estrogen-induced deoxyribonucleic acid damage. Mol Endocrinol 17: 1344-1355.
Coles AH, Jones SN (2009). The ING gene family in the regulation of cell growth and tumorigenesis. J Cell Physiol 218: 45-57.
Doyon Y, Cayrou C, Ullah M, Landry AJ, Coté, V, Selleck W, Lane WS, Tan S, Yang XJ, Coté J (2006). ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell 21: 51-64.
Feng X, Hara Y, Riabowol K (2002). Different HATS of the ING1 gene family. Trends Cell Biol 12: 532-538.
Garkavtsev I, Kazarov A, Gudkov A, Riabowol K (1996). Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. Nat Genet 14: 415-20.
Iso T, Watanabe T, Iwamoto T, Shimamoto A, Furuichi Y (2006). DNA damage caused by bisphenol A and estradiol through estrogenic activity. Biol Pharm Bull 29: 206-210.
Kataoka H, Bonnefin P, Vieyra D, Feng X, Hara Y, Miura Y, Joh T, Nakabayashi H, Vaziri H, Harris CC et al. (2003). ING1 represses transcription by direct DNA binding and through effects on p53. Cancer Res 63: 5785-5792.
Kuo WHW, Wang Y, Wong RPC, Campos EI, Li G (2007). The ING1b tumor suppressor facilitates nucleotide excision repair by promoting chromatin accessibility to XPA. Exp Cell Res 313: 1628-1638.
Li N, Li Q, Cao X, Zhao G, Xue L, Tong T (2011). The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence. FEBS Lett 585: 3106-3112.
Margueron R, Duong V, Castet A, Cavaillès V (2004). Histone deacetylase inhibition and estrogen signalling in human breast cancer cells. Biochem Pharmacol 68: 1239-1246.
Mobley JA, Brueggemeier RW (2004). Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer. Carcinogenesis 25: 3-9.
Nouman GS, Anderson JJ, Crosier S, Shrimankar J, Lunec J, Angus B (2003a). Downregulation of nuclear expression of the p33(ING1b) inhibitor of growth protein in invasive carcinoma of the breast. J Clin Pathol 56: 507-11.
Nouman GS, Anderson JJ, Lunec J, Angus B (2003b). The role of the tumour suppressor p33ING1b in human neoplasia. J Clin Pathol 56: 491-496.
Nouman GS, Anderson JJ, Mathers ME, Leonard N, Crosier S, Lunec J, Angus B (2002a). Nuclear to cytoplasmic compartment shift of the p33ING1b tumour suppressor protein is associated with malignancy in melanocytic lesions. Histopathology 40: 360- 366.
Nouman GS, Anderson JJ, Wood KM, Lunec J, Hall AG, Reid MM, Angus B (2002b). Loss of nuclear expression of the p33ING1b inhibitor of growth protein in childhood acute lymphoblastic leukaemia. J Clin Pathol 55: 596-601.
Russell M, Berardi P, Gong W, Riabowol K (2006). Grow-ING, AgeING and Die-ING: ING proteins link cancer, senescence and apoptosis. Exp Cell Res 312: 951-61.
Sayan B, Cevdet N, Emre T, Irmak MB (2009). Nuclear exclusion of p33ING1b tumor suppressor protein: explored in HCC cells using a new highly specific antibody. Hybridoma 28: 5-10.
Toyama T, Iwase H, Yamashita H, Hara Y, Sugiura H, Zhang Z, Fukai I, Miura Y, Riabowol K, Fujii Y (2003). p33ING1b stimulates the transcriptional activity of the estrogen receptor via its activation function (AF) 2 domain. J Steroid Biochem Mol Biol 87: 57-63.
Zhang JT, Wang DW, Li QX, Zhu ZL, Wang MW, Cui DS, Yang YH, Gu YX, Sun XF (2008). Nuclear to cytoplasmic shift of p33ING1b protein from normal oral mucosa to oral squamous cell carcinoma in relation to clinicopathological variables. J Cancer Res Clin Oncol 134: 421-426.
Zhu ZL, Yan BY, Zhang Y, Yang YH, Wang ZM, Zhang HZ, Wang MW, Zhang XH, Sun XF (2012). Cytoplasmic expression of p33ING1b is correlated with tumorigenesis and progression of human esophageal squamous cell carcinoma. Oncol Lett 5: 161-166.