title: Autocrine human growth hormone reduces mammary and endometrial carcinoma cell sensitivity to mitomycin C.
abstract: Drug resistance is a major cause of chemotherapy failure in breast cancer patients with metastatic disease. We previously demonstrated that autocrine human growth hormone (hGH) plays a key role in oncogenic transformation and progression of mammary carcinoma. The present study investigated the role of autocrine hGH in the development of resistance to mitomycin C (MMC), an alkylating agent utilised in the treatment of advanced metastatic breast cancer. Stable forced expression of the hGH gene was established in the mammary carcinoma cell lines MDA-MB-231, MCF-7 and T47D. Autocrine hGH reduced the sensitivity of mammary carcinoma cells to MMC in cell viability assays and reduced MMC-induced apoptotic cell death when compared to a control cell line. In addition, autocrine hGH enhanced MDA-MB-231 clonogenic survival, anchorage independent cell growth, growth in 3D Matrigel and protected MDA-MB-231 cells from induction of DNA double-strand breaks following MMC treatment. Functional antagonism of hGH in the endometrial carcinoma cell line RL95-2, which endogenously expresses hGH, significantly increased the sensitivity of these cells to MMC-induced DNA damage and cell death. Thus, autocrine hGH promotes mammary and endometrial carcinoma cell resistance to MMC. These studies indicate a potential role for antagonism of autocrine hGH in chemoresistant breast cancer.
authors.affiliation: Liggins Institute, University of Auckland, Auckland 1023, New Zealand.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Bougen
authors.forename: Teresa
authors.initials: T
authors.lastname: Yang
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lobie
authors.forename: Jo K
authors.initials: JK
authors.lastname: Perry
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004351:Drug Resistance; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D019382:Human Growth Hormone / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D014162:Transfection
chemical_list: D019382:Human Growth Hormone; D016685:Mitomycin