Human growth hormone-regulated HOXA1 is a human mammary epithelial oncogene.
Increased mammary epithelial expression of the human growth hormone (hGH) gene is associated with the acquisition of pathological proliferation. We report here that autocrine hGH production by human mammary carcinoma cells increased the expression and transcriptional activity of the homeobox domain containing protein HOXA1. Forced expression of HOXA1 in human mammary carcinoma cells resulted in increased total cell number primarily by the promotion of cell survival mediated by the transcriptional up-regulation of Bcl-2. HOXA1 also abrogated the apoptotic response of mammary carcinoma cells to doxorubicin. Forced expression of HOXA1 in mammary carcinoma cells, in a Bcl-2-dependent manner, resulted in dramatic enhancement of anchorage-independent proliferation and colony formation in soft agar. Finally, forced expression of HOXA1 was sufficient to result in the oncogenic transformation of immortalized human mammary epithelial cells with aggressive in vivo tumor formation. Herein, we have therefore provided a molecular mechanism by which autocrine hGH stimulation of human mammary epithelial cells may result in oncogenic transformation.
Zhang
Xin
X
Institute of Molecular and Cell Biology and Department of Medicine, National University of Singapore, 30 Medical Dr., Singapore 117609, Republic of Singapore.
Zhu
Tao
T
Chen
Yong
Y
Mertani
Hichem C
HC
Lee
Kok-Onn
KO
Lobie
Peter E
PE
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism*; D017930:Genes, Reporter; D018398:Homeodomain Proteins / Q000378:metabolism* / Q000502:physiology*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000099261:Homeobox A1 Protein
D000963:Antimetabolites; D000970:Antineoplastic Agents; D001973:Bromodeoxyuridine; D018076:DNA, Complementary; D004317:Doxorubicin; D018398:Homeodomain Proteins; D019382:Human Growth Hormone; D008156:Luciferases; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014157:Transcription Factors; D000099261:Homeobox A1 Protein