Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1

Mol Cell Biol. 2006 Sep;26(17):6412-24. doi: 10.1128/MCB.01950-05.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / deficiency
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / pathology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Exons / genetics
  • G2 Phase / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • HeLa Cells
  • Humans
  • Mammary Glands, Animal / cytology
  • Mice
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Mitosis / drug effects*
  • Neuregulin-1 / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-4
  • Tumor Cells, Cultured

Substances

  • BRCA1 Protein
  • Neuregulin-1
  • RNA, Messenger
  • Mitogen-Activated Protein Kinase 9
  • ERBB4 protein, human
  • ErbB Receptors
  • Erbb4 protein, mouse
  • Receptor, ErbB-2
  • Receptor, ErbB-4
  • Mitogen-Activated Protein Kinase 8