Oncogenic transformation of human mammary epithelial cells by autocrine human growth hormone.
The human growth hormone (hGH) gene is expressed in the normal human mammary epithelial cell and its expression increases concomitant with the acquisition of proliferative lesions. Herein we demonstrate that autocrine production of hGH in human mammary carcinoma cells dramatically enhances anchorage-independent growth in a Janus kinase 2-dependent manner. Forced expression of the hGH gene in immortalized human mammary epithelial cells increased proliferation, decreased apoptosis, altered the cellular morphology and resulted in oncogenic transformation. Autocrine hGH was therefore sufficient to support anchorage-independent growth of immortalized human mammary epithelial cells and tumor formation in vivo. Moreover, autocrine hGH disrupted normal mammary acinar architecture with luminal filling and deregulated proliferation in three-dimensional epithelial cell culture. Autocrine hGH utilized homeobox A1 to govern the transcriptional program required for autocrine hGH-stimulated oncogenic transformation of human mammary epithelial cells, including transcriptional up-regulation of c-Myc, cyclin D1, and Bcl-2. Forced expression of a single orthotopically expressed wild-type gene is therefore sufficient for oncogenic transformation of the immortalized human mammary epithelial cell.
Zhu
Tao
T
Institute of Molecular and Cell Biology, National University of Singapore, Singapore, Republic of Singapore.
Starling-Emerald
B
B
Zhang
Xin
X
Lee
Kok-Onn
KO
Gluckman
Peter D
PD
Mertani
Hichem C
HC
Lobie
Peter E
PE
D001940:Breast / Q000166:cytology* / Q000473:pathology*; D001943:Breast Neoplasms; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology; D005260:Female; D016259:Genes, myc; D005822:Genetic Vectors; D019382:Human Growth Hormone / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection
D017931:DNA Primers; D019382:Human Growth Hormone; D019938:Cyclin D1