Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1
| Autor: | H. Shelton Earp, Karen E. Strunk, Rebecca S. Muraoka-Cook, Wesley McCall, Kenneth H. Cowan, Magdalene K. Sgagias, Melissa Sandahl, Laura S. Caskey, Debra Hunter, Carty Husted, Carolyn I. Sartor, William A. Rearick |
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| Rok vydání: | 2006 |
| Předmět: |
G2 Phase
Small interfering RNA animal structures Receptor ErbB-4 Receptor ErbB-2 Neuregulin-1 Mitosis Breast Neoplasms Biology chemistry.chemical_compound Mice Mammary Glands Animal medicine Tumor Cells Cultured Animals Humans Mitogen-Activated Protein Kinase 9 Mitogen-Activated Protein Kinase 8 RNA Messenger skin and connective tissue diseases Molecular Biology Cell growth BRCA1 Protein Cancer Epithelial Cells Cell Biology Exons Articles Cell cycle medicine.disease ErbB Receptors Gene Expression Regulation Neoplastic chemistry Cell culture Cancer research Neuregulin Growth inhibition HeLa Cells |
| Zdroj: | Molecular and cellular biology. 26(17) |
| ISSN: | 0270-7306 |
| Popis: | HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1. |
| Databáze: | OpenAIRE |
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