title: Suppression of Akt-mTOR pathway-a novel component of oncogene induced DNA damage response barrier in breast tumorigenesis.
abstract: DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized 'normal-like' breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Anjana
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rosen
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Nivetha
authors.initials: N
authors.lastname: Ganesan
authors.affiliation: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Etzel
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Ashley
authors.initials: A
authors.lastname: Gullett
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Constance T
authors.initials: CT
authors.lastname: Albarracin
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bedrosian
mesh_terms: D001343:Autophagy; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019927:Cyclin E / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000473:pathology; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012306:Risk; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D019927:Cyclin E; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases