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Heregulin ß1-activated Phosphatidylinositol 3-Kinase Enhances Aggregation of MCF-7 Breast Cancer Cells Independent of Extracellular Signal-regulated Kinase¹

From the Department of Surgical Oncology and The Breast Cancer Basic Research Program, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Heregulin (HRG) is a family of polypeptide growth factors derived from alternatively spliced genes. HRG can bind to receptor tyrosine kinases erbB3 and erbB4, thereby inducing erbB3 and erbB4 heterodimerization with erbB2, leading to receptor tyrosine phosphorylation and activating downstream signal transduction. Cell-cell homophilic adhesion (cell aggregation) is important in determining the structural organization and behavior of cells in tissues. In addition, tumor cell homophilic adhesion may affect invasive and metastatic potentials of cells. We report that HRG-ß1 can enhance aggregation of MCF-7 and SKBR3 human breast cancer cells. While investigating the downstream signals involved in HRG-ß1-enhanced cell aggregation, we observed that HRG-ß1 induced tyrosine phosphorylation of erbB2 and erbB3 receptor heterodimers and increased the association of the dimerized receptors with the 85-kDa subunit of phosphatidylinositol 3-kinase (PI3K). HRG-ß also increased the kinase activities of extracellular signal-regulated protein kinase (ERK) and PI3K in these cells. By using the mitogen-activated protein kinase/ERK 1 (MEK1) inhibitor PD98059 and PI3K inhibitors wortmannin and LY294002, we found that blocking the MEK1-ERK pathway had no effect on HRG-ß1-enhanced cell aggregation; however, blocking the PI3K pathway greatly inhibited HRG-ß1-mediated cell aggregation. Our study indicated that the HRG-ß1-activated MEK1-ERK pathway has no demonstrable role in the induction of cell aggregation, whereas HRG-ß1-activated PI3K is required for enhancing breast cancer cell aggregation. Because aggregation can contribute to invasion/metastasis phenotype of cancer cells, our results have provided one mechanism by which HRG-ß1-activated signaling of erbB receptors may affect invasive/metastatic properties of MCF-7 and SKBR3 breast cancer cells.

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