title: Autocrine human growth hormone increases sensitivity of mammary carcinoma cell to arsenic trioxide-induced apoptosis.
abstract: Human growth hormone (hGH) has been increasingly implicated in a variety of cancers; its up-regulation is observed in breast cancer and correlates with a poor outcome. Autocrine hGH promotes mammary carcinoma cell survival, proliferation, immortalization; it confers an invasive phenotype as a result of an epithelial-mesenchymal transition and contributes to chemoresistance and radioresistance. Arsenic trioxide (ATO) is being successfully used as a first and second line therapy for the treatment of patients with acute promyelocytic leukemia. It also inhibits tumor cell growth and induces apoptosis in a broad range of solid tumors. In the present study, we investigated the effect of hGH on sensitivity of a mammary adenocarcinoma cell to ATO, using a stable hGH-transfectant MCF-7 cell line, MCF7-hGH. Our results demonstrated for the first time that the overexpression of hGH increased sensitivity of the breast cancer cell line MCF-7 to ATO through apoptotic and anti-proliferative mechanisms. The effect of ATO on the transcriptional level of genes involved in survival (Bcl-2, Bax and Survivin), self-sufficiency in growth signals (c-Myc, ARF, Cdc25A, p53 and Bax), immortalization (hTERT) and invasion and metastasis (MMP-2 and MMP-9, uPA and uPAR and E-cadherin) was more pronounced in MCF7-hGH compared with its parental MCF-7 line. Our study may highlight the potential application of ATO for the treatment of patients with breast cancer, especially in those who have metastatic and chemoresistant tumor phenotype possibly due to the over expression of hGH.
authors.affiliation: Hematology, Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Zekri
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Ghaffari
authors.forename: Meysam
authors.initials: M
authors.lastname: Yousefi
authors.forename: Samad
authors.initials: S
authors.lastname: Ghanizadeh-Vesali
authors.forename: Majid
authors.initials: M
authors.lastname: Mojarrad
authors.forename: Kamran
authors.initials: K
authors.lastname: Alimoghaddam
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Ghavamzadeh
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010087:Oxides / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D001152:Arsenicals; D010087:Oxides; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D019382:Human Growth Hormone; D020782:Matrix Metalloproteinases; D000077237:Arsenic Trioxide
keywords: Apoptosis; Arsenic trioxide; Autocrine human growth hormone; Breast cancer; Mammary adenocarcinoma; c-Myc