{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T14:36:05Z","timestamp":1759588565168},"reference-count":24,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,2,4]],"date-time":"2005-02-04T00:00:00Z","timestamp":1107475200000},"content-version":"vor","delay-in-days":3536,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[1995,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recently, a family of growth factors has been described that activates erbB\u20102 receptors. These factors, known as the neu differentiation factors (NDF) or heregulins (HRG), induce tyrosine phosphorylation of erbB\u20102 receptors as a result of their direct interaction with either erbB\u20103 or erbB\u20104 receptors. Although it is known that expression of erbB\u20102 receptors has relevance in human breast cancer progression, how erbB\u20102, \u20103 and \u20104 receptors regulate mammary epithelial cell proliferation is not known. Therefore, experiments were carried out to study the mitogenic activity of NDF\/HRG on the human mammary epithelial cell line MCF\u201010A which can be cultured continuously under serum\u2010free conditions. MCF\u201010A cells, like primary cultures of normal human mammary epithelial cells, express an absolute requirement for exogenous epidermal growth factor (EGF) and insulin\u2010like growth factor I (IGF\u2010I) for growth. The results of these experiments indicate that NDF\/HRG can induce tyrosine phosphorylation of p185erbB\u20102 in MCF\u201010A cells and is mitogenic for these cells. This is consistent with the coexpression of erbB\u20102 and erbB\u20103 mRNA that we have observed in MCF\u201010A cells. In addition, we found that NDF\/HRG can substitute for either EGF or IGF\u2010I to stimulate proliferation of these cells. The ability to substitute for both EGF and IGF\u2010I is a unique property of NDF\/HRG and is not shared by other members of the EGF or IGF family of growth factors, nor by other factors that we have studied. A striking isoform specificity was also observed which indicated that the \u03b2\u2010isoforms of NDF\/HRG were greater than ten times more mitogenic than the \u03b1\u2010isoforms. We also examined the mitogenic activity of NDF\/HRG on MCF\u201010A cells that overexpress the erbB\u20102 receptor as a result of infection with a retroviral vector containing the human c\u2010erbB\u20102 gene (MCF\u201010AerbB\u20102 cells). These studies indicated that MCF\u201010AerbB\u20102 cells have increased sensitivity to the mitogenic effects of NDF\/HRG and that these cells are responsive to the \u03b1\u2010isoforms of NDF\/HRG at physiological concentrations. Thus, NDF\/HRG is a dual specificity growth factor for human mammary epithelial cells, and the responsiveness of the cells to NDF\/HRG is influenced by the level of expression of erbB\u20102 receptors. \u00a9 1995 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.1041630320","type":"journal-article","created":{"date-parts":[[2005,2,26]],"date-time":"2005-02-26T04:18:14Z","timestamp":1109391494000},"page":"589-596","source":"Crossref","is-referenced-by-count":43,"title":["Mitogenic activity of neu differentiation factor\/heregulin mimics that of epidermal growth factor and insulin\u2010like growth factor\u2010I in human mammary epithelial cells"],"prefix":"10.1002","volume":"163","author":[{"given":"Tracy G.","family":"Ram","sequence":"first","affiliation":[]},{"given":"Kristine E.","family":"Kokeny","sequence":"additional","affiliation":[]},{"given":"Cheryl A.","family":"Dilts","sequence":"additional","affiliation":[]},{"given":"Stephen P.","family":"Ethier","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2005,2,4]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"crossref","first-page":"8204","DOI":"10.1016\/S0021-9258(18)53083-0","article-title":"Association of IRS\u2010I with the insulin receptor and phosphadityl inositol\u20103 kinase","volume":"268","author":"Backer J. M.","year":"1993","journal-title":"J. Biol. Chem."},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36789-3"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.2940060108"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01980969"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041320123"},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01806371"},{"key":"e_1_2_1_8_1","first-page":"593","article-title":"Secretion of an epidermal growth factor\u2010like growth factor by epidermal growth factor\u2010independent rat mammary carcinoma cells","volume":"2","author":"Ethier S. 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