c-Myc alters the DNA damage-induced G2 M arrest in human mammary epithelial cells

• Published in: British journal of cancer Vol. 89; no. 8; pp. 1479 - 1485
• Main Authors: SHEEN, J-H, WOO, J-K, DICKSON, R. B
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 20.10.2003
• Subjects: Apoptosis; Biological and medical sciences; Blotting, Western; Breast - cytology; Breast - pathology; Cancer research; Cell Differentiation; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Chromosomes; DNA Damage; Epithelial Cells - physiology; Female; Fundamental and applied biological sciences. Psychology; G2 Phase; Genes, cdc; Humans; Immunohistochemistry; Kinases; Medical research; Mitosis; Molecular and cellular biology; Molecular and Cellular Pathology; Oligonucleotide Array Sequence Analysis; Phenotype; Proto-Oncogene Proteins c-myc - biosynthesis; Proto-Oncogene Proteins c-myc - pharmacology; Radiation; Human; Mitosis; c-Myc; DNA damage; Ionizing irradiation; ionising radiation; human mammary epithelial cells; Shutdown; DNA; C-Onc gene; Cell cycle; G2 Phase; G2/M checkpoint; cyclin B1; Genetics; Epithelial cell; Mammary gland; Lesion; Control point; Protooncogene
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601307

Effects of c-Myc overexpression on the DNA damage-induced G2/M checkpoint were studied in finite lifespan, normal human mammary epithelial cells (HMECs). Previously, we showed that c-Myc attenuates G1/S arrest and leads to an inappropriate entry of cells with damaged DNA into the S phase, following treatment with ionising radiation (IR). Here we show that, in striking contrast to control cells, c-Myc-overexpressing HMECs demonstrate a significant attenuation of the G2/M arrest, following IR, and enter into inappropriate mitoses. At the molecular level, ectopic overexpression of c-Myc leads to an unusually high level of expression of cyclin B1, and the elevated levels of cyclin B1 were maintained, after gamma-irradiation. Introduction of DNA damage in c-Myc-overexpressing, normal mammary epithelial cells eventually induces apoptosis, indicating a dramatic sensitisation by c-Myc of DNA damage-induced apoptosis. These two remarkable phenotypes, checkpoint attenuation and sensitisation to apoptosis, resulting from a deregulation of the protooncogene c-myc, may produce a unique pattern of alternating cycles, consisting first of amplification of DNA damage, followed by apoptosis-assisted selective pressure. The result of this alternating pattern of damage apoptosis could facilitate the selection of certain genomic alterations required for cellular survival and cellular transformation.