Phenotypic conversion of human mammary carcinoma cells by autocrine human growth hormone
- Svetlana Mukhina*,
- Hichem C. Mertani†,
- Ke Guo*,
- Kok-Onn Lee‡,
- Peter D. Gluckman§, and
- Peter E. Lobie*,§,¶
- *Institute of Molecular and Cell Biology, 30 Medical Drive, Republic of Singapore 117609; †Centre National de la Recherche Scientifique, Unité Mixte de Recherche, 5123 Physiologie Moléculaire, Université Claude Bernard Lyon 1, Bātiment 404, R Dubois, 3ième Étage, 43 Boulevard du 11 Novembre 1918, 69 622 Villeurbanne Cedex, France; ‡Department of Medicine, National University of Singapore, Republic of Singapore 119074; and §Liggins Institute and National Research Centre for Growth and Development, University of Auckland, 2-6 Park Avenue, Private Bag 92019, Auckland, New Zealand
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Communicated by Melvin M. Grumbach, University of California, San Francisco, CA, August 12, 2004 (received for review December 18, 2003)
Abstract
We report here that autocrine production of human growth hormone (hGH) results in a phenotypic conversion of mammary carcinoma cells such that they exhibit the morphological and molecular characteristics of a mesenchymal cell, including expression of fibronectin and vimentin. Autocrine production of hGH resulted in reduced plakoglobin expression and relocalization of E-cadherin to the cytoplasm, leading to dissolution of cell-cell contacts and decreased cell height. These phenotypic changes were accompanied by an increase in cell motility, elevated activity of specific matrix metalloproteinases, and an acquired ability to invade a reconstituted basement membrane. Forced expression of plakoglobin significantly decreased mammary carcinoma cell migration and invasion stimulated by autocrine hGH. In vivo, autocrine hGH stimulated local invasion of mammary carcinoma cells concomitant with a prominent stromal reaction in comparison with well delineated and capsulated growth of mammary carcinoma cells lacking autocrine production of hGH. Thus, autocrine production of hGH by mammary carcinoma cells is sufficient for generation of an invasive phenotype. Therapeutic targeting of autocrine hGH may provide a mechanistic approach to prevent metastatic extension of human mammary carcinoma.
