MITOGENIC ACTIVITY OF NET DIFFERENTIATION FACTOR HEREGULIN MIMICS THAT OF EPIDERMAL GROWTH-FACTOR AND INSULIN-LIKE GROWTH-FACTOR-I IN HUMAN MAMMARY EPITHELIAL-CELLS

被引：62

作者：

RAM, TG ^{[1
]}

KOKENY, KE ^{[1
]}

DILTS, CA ^{[1
]}

ETHIER, SP ^{[1
]}

机构：

[1] UNIV MICHIGAN,SCH MED,DEPT RADIAT ONCOL,DIV RADIAT & CANC BIOL,ANN ARBOR,MI 48109

来源：

JOURNAL OF CELLULAR PHYSIOLOGY | 1995年 / 163卷 / 03期

关键词：

D O I：

10.1002/jcp.1041630320

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Recently, a family of growth factors has been described that activates erbB-2 receptors. These factors, known as the neu differentiation factors (NDF) or heregulins (HRG), induce tyrosine phosphorylation of erbB-2 receptors as a result of their direct interaction with either erbB-3 or erbB-4 receptors. Although it is known that expression of erbB-2 receptors has relevance in human breast cancer progression, how erbB-2, -3 and -4 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-10A which can be cultured continuously under serum-free conditions. MCF-10A cells, like primary cultures of normal human mammary epithelial cells, express an absolute requirement for exogenous epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) for growth. The results of these experiments indicate that NDF/HRG can induce tyrosine phosphorylation of p185erbB-2 in MCF-10A cells and is mitogenic for these cells. This is consistent with the coexpression of erbB-2 and erbB-3 mRNA that we have observed in MCF-10A cells. in addition, we found that NDF/HRG can substitute for either EGF or IGF-I to stimulate proliferation of these cells. The ability to substitute for both EGF and IGF-I 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 beta-isoforms of NDF/HRG were greater than ten times more mitogenic than the alpha-isoforms. We also examined the mitogenic activity of NDF/HRG on MCF-1OA cells that overexpress the erbB-2 receptor as a result of infection with a retroviral vector containing the human c-erbB-2 gene (MCF-10AerbB-2 cells). These studies indicated that MCF-10AerbB-2 cells have increased sensitivity to the mitogenic effects of NDF/HRG and that these cells are responsive to the alpha-isoforms 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-2 receptors. (C) 1995 Wiley-Liss, Inc.

引用

页码：589 / 596

页数：8

共 24 条

[1]

Backer J.M., Myers M.G., Sun X.J., Chen D.J., Shoelson S.E., Mivalpeix M., White M.F., Association of IRS‐I with the insulin receptor and phosphadityl inositol‐3 kinase, J. Biol. Chem., 268, pp. 8204-8212, (1993)

[2]

Carraway K.L., Sliwkowski M.X., Akita R., Platko J.V., Guy P.M., Nuijens A., Diamonti A.J., Vandlen R.L., Cantley L.C., Cerione R.A., The erbB3 gene product is a receptor for heregulin, J. Biol. Chem., 269, pp. 14303-14306, (1994)

[3]

Ciardiello F., Gottardis M., Basolo F., Pepe S., Normanno N., Dickson R.B., Bianco A.R., Salomon D.S., Additive effects of c‐erbB‐2, c‐Ha‐ras, and transforming growth factor‐alpha genes on in vitro transformation of human mammary epithelial cells, Mol. Carcinogen., 6, pp. 43-52, (1992)

[4]

Ethier S.P., Moorthy R., Multiple growth factor independence in rat mammary carcinoma cells, Breast Cancer Res. Treat., 18, pp. 73-81, (1991)

[5]

Ethier S.P., Kudla A., Cundiff K.C., The influence of hormone and growth factor interactions on the proliferative potential of normal rat mammary epithelial cells in vitro, J. Cell. Physiol., 132, pp. 161-167, (1987)

[6]

Ethier S.P., Summerfelt R.M., Cundiff K.C., Asch B.B., The influence of growth factors on the proliferative potential of normal and primary breast cancer‐derived human breast epithelial cells, Breast Cancer Res. Treat., 17, pp. 221-230, (1990)

[7]

Ethier S.P., Moorthy R., Dilts C.A., Secretion of an epidermal growth factor‐like growth factor by epidermal growth factor‐independent rat mammary carcinoma cells, Cell Growth Differ, 2, pp. 593-602, (1991)

[8]

Fedi P., Pierce J.H., Difiore P.P., Kraus M.H., Efficient coupling with phosphatidylinositol 3‐kinase, but not phospholipase C gamma or GTPase‐activating protein, distinguishes erbB‐3 signaling from that of other erbB EGFr family members, Mol. Cell. Biol., 14, pp. 492-500, (1994)

[9]

Hammond S.L., Ham R.G., Stampfer M.R., Serum‐free growth of human mammary epithelial cells: Rapid clonal growth in defined medium and extended serial passage with pituitary extract, Proc. Natl. Acad. Sci. U.S.A., 81, pp. 5435-5439, (1984)

[10]

Holmes W.E., Sliwkowski M.X., Akita R.W., Henzel W.J.J.L., Park J.W., Yansura D., Abadi N., Raab H., Lewi G.D., Shepard M., Kuang W.-J., Wood W.I., Goeddel D.V., Vandlen R.L., Identification of heregulin, a specific activator of p185erbB2, Science, 256, pp. 1205-1210, (1992)

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