The hGH gene is expressed in epithelial cells of the normal human mammary gland. Increased epithelial expression of the hGH gene is associated with the acquisition of pathological proliferation, and the highest level of hGH gene expression is observed in metastatic mammary carcinoma cells. Autocrine hGH production in human mammary carcinoma cells results in increased cell proliferation and survival associated with alterations in morphology. We have further demonstrated that autocrine production of hGH in immortalized human mammary epithelial cells concomitantly enhances proliferation and offers protection from apoptosis; forming the basis for abnormal mammary acinar morphogenesis, oncogenic transformation and tumor formation in vivo. Thus, simple forced expression the hGH gene is sufficient for oncogenic transformation of the immortalized human mammary epithelial cell. Moreover, autocrine production of hGH, in mammary carcinoma cells with epithelial morphology, promotes mesenchymal cellular morphology, increased cell migration and increased metalloprotease (MMP) activity with subsequent acquisition of invasive behavior both in vitro and in vivo. Autocrine hGH also increases mammary carcinoma VEGF expression resulting in paracrine induced endothelial cell proliferation, survival, migration/invasion, tube formation and increased tumor angiogenesis in vivo. In stark contrast to the oncogenic and metastatic potential of autocrine hGH, exogenous hGH neither supports tumor formation nor invasion by human mammary epithelial cells. We have utilized this discrepancy in the oncogenicity of autocrine and exogenous hGH to identify two autocrine hGH regulated genes, trefoil factors 1 and 3 (TFF1/3), that mediate the oncogenic effects of autocrine hGH in human mammary carcinoma cells. We therefore postulate that autocrine hGH functions as a higher order switch, controlling at least some of the genetic elements required for oncogenic transformation and neoplastic progression of the human mammary epithelial cell.
03 - 07 May 2008
European Society of Endocrinology