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Endocrinology Vol. 142, No. 2 767-777
Copyright © 2001 by The Endocrine Society

ARTICLES

The Effects of Autocrine Human Growth Hormone (hGH) on Human Mammary Carcinoma Cell Behavior Are Mediated via the hGH Receptor1

Karmal K. Kaulsay2, Tao Zhu2, William F. Bennett, Kok-Onn Lee and Peter E. Lobie

Department of Medicine, National University of Singapore (K.K.K., K.O.L.), Singapore 119074, Republic of Singapore; and Institute of Molecular and Cell Biology (T.Z., P.E.L.), Singapore 117609, Republic of Singapore; and Sensus Drug Development Corporation (W.F.B.), Austin, Texas 78701

Address all correspondence and requests for reprints to: Peter E. Lobie, M.D., Ph.D., Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Republic of Singapore. E-mail: mcbpel{at}imcb.nus.edu.sg

The human GH (hGH) antagonist B2036 combines a single amino acid substitution impairing receptor binding site 2 (G120K) with eight additional amino acid substitutions that improve binding site 1 affinity. B2036 does not bind, activate, or antagonize the human PRL receptor and therefore is suitable to determine cellular effects mediated specifically through the hGH receptor. We have used this hGH receptor specific antagonist in MCF-7 cells stably transfected with either the hGH gene (MCF-hGH) or a translation deficient hGH gene (MCF-MUT) to determine whether the effects of autocrine hGH on mammary carcinoma cell behavior are mediated via the hGH receptor. Enhanced JAK2 tyrosine phosphorylation observed in MCF-hGH cells compared with MCF-MUT cells is abrogated by B2036 as is the autocrine hGH stimulated increase in total cell number and DNA synthesis. Interestingly, autocrine hGH functions as a potent inhibitor of apoptosis induced by serum withdrawal compared with exogenously added hGH, and the protection against apoptosis afforded by autocrine hGH is abrogated by B2036. B2036 also inhibited autocrine hGH stimulated transcriptional activation mediated by either STAT5, CHOP (p38 MAP kinase specific) or Elk-1 (p44/42 MAP kinase specific). Finally, B2036 inhibited the autocrine hGH-dependent enhancement of the rate of mammary carcinoma cell spreading on a collagen matrix. Thus, the effects of autocrine hGH on human mammary carcinoma cell behavior are mediated via the hGH receptor.




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