Effect of hypoxia and TP53 mutation status and cytogenetics of normal and malignant mammary epithelium


      It has been proposed that hypoxia favors the growth of tumor cells over normal cells, particularly tumor cells carrying TP53 mutations. Cytogenetic studies of breast cancer have shown that highly complex karyotypes seen in direct harvest preparations are rarely detected after short-term culture. In this study, 34 paired samples of breast carcinomas and grossly nontumorous tissue from the same breast were cultured at 20 and 5% (12 samples) or 20 and 0% oxygen (22 samples). Both carcinoma samples and nontumorous tissue survived at 0% oxygen. Recovery for 24 hours at 20% produced good yields for cytogenetic analysis. Lower oxygen levels did not specifically stimulate growth of tumor cells. Samples with TP53 mutations showed a consistently increased growth under anaerobic hypoxic conditions. Culture at 5% oxygen did not generally reveal more karyotypic abnormalities than found at 20%. In the samples cultured at 0 and 20%, karyotypic abnormalities were detected only in anaerobic hypoxic culture in two cases. Of the only four samples where more complex karyotypes were detected in the low-oxygen culture, two were TP53 mutated. Hypoxic treatment followed by recovery at 20% oxygen may thus increase the yield of complex karyotypes from a subset of breast carcinomas, particularly those with mutated TP53.
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        • Knowles H.J.
        • Harris A.L.
        Hypoxia and oxidative stress in breast cancer: hypoxia and tumourigenesis.
        Breast Cancer Res. 2001; 3: 318-322
        • Brizel D.M.
        • Rosner G.L.
        • Prosnitz L.R.
        • Dewhirst M.W.
        Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases.
        Int J Radiat Oncol Biol Phys. 1995; 32: 1121-1125
        • Helmlinger G.
        • Yuan F.
        • Dellian M.
        • Jain R.K.
        Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation.
        Nat Med. 1997; 3: 177-182
        • Giatromanolaki A.
        • Sivridis E.
        • Koukourakis M.I.
        Tumour angiogenesis: vascular growth and survival.
        Apmis. 2004; 112: 431-440
        • Pennacchietti S.
        • Michieli P.
        • Galluzzo M.
        • Mazzone M.
        • Giordano S.
        • Comoglio P.M.
        Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene.
        Cancer Cell. 2003; 3: 347-361
        • Graeber T.G.
        • Osmanian C.
        • Jacks T.
        • Housman D.E.
        • Koch C.J.
        • Lowe S.W.
        • Giaccia A.J.
        Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.
        Nature. 1996; 379: 88-91
        • Helczynska K.
        • Kronblad A.
        • Jogi A.
        • Nilsson E.
        • Beckman S.
        • Landberg G.
        • Pahlman S.
        Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ.
        Cancer Res. 2003; 63: 1441-1444
        • Bergstraesser L.M.
        • Weitzman S.A.
        Culture of normal and malignant primary human mammary epithelial cells in a physiological manner simulates in vivo growth patterns and allows discrimination of cell type.
        Cancer Res. 1993; 53: 2644-2654
        • Dairkee S.H.
        • Deng G.
        • Stampfer M.R.
        • Waldman F.M.
        • Smith H.S.
        Selective cell culture of primary breast carcinoma.
        Cancer Res. 1995; 55: 2516-2519
        • Jogi A.
        • Ora I.
        • Nilsson H.
        • Lindeheim A.
        • Makino Y.
        • Poellinger L.
        • Axelson H.
        • Pahlman S.
        Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
        Proc Natl Acad Sci U S A. 2002; 99: 7021-7026
        • Steinarsdottir M.
        • Petursdottir I.
        • Snorradottir S.
        • Eyfjord J.E.
        • Ogmundsdottir H.M.
        Cytogenetic studies of breast carcinomas: different karyotypic profiles detected by direct harvesting and short-term culture.
        Genes Chromosomes Cancer. 1995; 13: 239-248
        • Steinardottir M.
        • Jonasson J.G.
        • Petursdottir I.
        • Sigurdsson H.
        • Ogmundsdottir H.M.
        A comparison of cytogenetic studies and flow cytometry in breast carcinomas.
        Cytometry. 1997; 28: 323-328
        • Pandis N.
        • Heim S.
        • Bardi G.
        • Limon J.
        • Mandahl N.
        • Mitelman F.
        Improved technique for short-term culture and cytogenetic analysis of human breast cancer.
        Genes Chromosomes Cancer. 1992; 5 ([Erratum in: Genes Chromosomes Cancer 1992;5:410]): 14-20
        • Gudjonsson T.
        • Villadsen R.
        • Nielsen H.L.
        • Ronnov-Jessen L.
        • Bissell M.J.
        • Petersen O.W.
        Isolation, immortalization, and characterization of a human breast epithelial cell line with stem cell properties.
        Genes Dev. 2002; 16: 693-706
        • Gudlaugsdottir S.
        • Sigurdardottir V.
        • Snorradottir M.
        • Jonasson J.G.
        • Ogmundsdottir H.
        • Eyfjord J.E.
        P53 mutations analysis in benign and malignant breast lesions: using needle rinses from fine-needle aspirations.
        Diagn Cytopathol. 2000; 22: 268-274
        • Hammond E.M.
        • Giaccia A.J.
        The role of p53 in hypoxia-induced apoptosis.
        Biochem Biophys Res Commun. 2005; 331: 718-725
        • Artandi S.E.
        • Attardi L.D.
        Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer.
        Biochem Biophys Res Commun. 2005; 331: 881-890
        • Bertrand P.
        • Saintigny Y.
        • Lopez B.S.
        p53's double life: transactivation-independent repression of homologous recombination.
        Trends Genet. 2004; 20 ([Erratum in: Trends Genet 2005;21:36]): 235-243
        • Duensing A.
        • Duensing S.
        Guilt by association? p53 and the development of aneuploidy in cancer.
        Biochem Biophys Res Commun. 2005; 331: 694-700
        • Gretarsdottir S.
        • Thorlacius S.
        • Valgardsdottir R.
        • Gudlaugsdottir S.
        • Sigurdsson S.
        • Steinarsdottir M.
        • Jonasson J.G.
        • Anamthawat-Jonsson K.
        • Eyfjord J.E.
        BRCA2 and p53 mutations in primary breast cancer in relation to genetic instability.
        Cancer Res. 1998; 58: 859-862
        • Smalley M.
        • Ashworth A.
        Stem cells and breast cancer: a field in transit.
        Nat Rev Cancer. 2003; 3: 832-844
        • Pardal R.
        • Clarke M.F.
        • Morrison S.J.
        Applying the principles of stem-cell biology to cancer.
        Nat Rev Cancer. 2003; 3: 895-902
        • Al-Hajj M.
        • Wicha M.S.
        • Benito-Hernandez A.
        • Morrison S.J.
        • Clarke M.F.
        Prospective identification of tumorigenic breast cancer cells.
        Proc Natl Acad Sci U S A. 2003; 100 ([Erratum in: Proc Natl Acad Sci U S A 2003;100:6890]): 3983-3988
        • Kleivi K.
        • Lothe R.A.
        • Heim S.
        • Tsarouha H.
        • Kraggerud S.M.
        • Pandis N.
        • Papadopoulou A.
        • Andersen J.
        • Jakobsen K.S.
        • Teixeira M.R.
        Genome profiling of breast cancer cells selected against in vitro shows copy number changes.
        Genes Chromosomes Cancer. 2002; 33: 304-309
      1. ISCN 1995: an international system for human cytogenetic nomenclature (1995).
        in: Mitelman F. S. Karger, Basel1995