Autocrine human GH promotes radioresistance in mammary and endometrial carcinoma cells.
Although recent advances in breast cancer treatment regimes have improved patient prognosis, resistance to breast cancer therapies, such as radiotherapy, is still a major clinical challenge. In the current study, we have investigated the role of autocrine human GH (hGH) in resistance to ionising radiation (IR)-based therapy. Cell viability and total cell number assays demonstrated that autocrine hGH promoted cell regrowth in the mammary carcinoma cell lines, MDA-MB-435S and T47D, and the endometrial carcinoma cell line, RL95-2, following treatment with IR. In addition, autocrine hGH enhanced MDA-MB-435S and T47D cell clonogenic survival following radiation exposure. The enhanced clonogenic survival afforded by autocrine hGH was mediated by JAK2 and Src kinases. Investigation into the DNA repair capacity demonstrated that autocrine hGH reduced IR-induced DNA damage in MDA-MB-435S and T47D cells. Functional antagonism of hGH increased RL95-2 sensitivity to IR in cell viability and total cell number assays, reduced clonogenic survival and enhanced the induction of DNA damage. Thus, autocrine hGH reduced sensitivity to treatment with IR in mammary and endometrial carcinoma cell lines in vitro, while functional antagonism of hGH sensitised endometrial carcinoma cells to IR. Functional antagonism of hGH, used in conjunction with radiotherapy, may therefore enhance treatment efficacy and improve the prognosis of patients with breast and endometrial cancer.
The Liggins Institute, University of Auckland, Auckland, New Zealand.
Nicola M
NM
Bougen
Michael
M
Steiner
Mikhail
M
Pertziger
Arindam
A
Banerjee
Severine E
SE
Brunet-Dunand
Tao
T
Zhu
Peter E
PE
Lobie
Jo K
JK
Perry
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019382:Human Growth Hormone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C422172:B 2036; D011837:Radiation-Protective Agents; D019382:Human Growth Hormone