Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1

Rebecca S. Muraoka-Cook, Laura S. Caskey, Melissa A. Sandahl, Debra M. Hunter, Carty Husted, Karen E. Strunk, Carolyn I. Sartor, William A. Rearick, Wesley McCall, Magdalene K. Sgagias, Kenneth H Cowan, H. Shelton Earp

Research output: Contribution to journalArticle

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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 G2/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.

Original languageEnglish (US)
Pages (from-to)6412-6424
Number of pages13
JournalMolecular and cellular biology
Volume26
Issue number17
DOIs
StatePublished - Sep 1 2006

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Neuregulin-1
Breast Neoplasms
Breast
JNK Mitogen-Activated Protein Kinases
Epithelial Cells
Cell Line
Growth
Small Interfering RNA
Exons
Cell Cycle
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Muraoka-Cook, R. S., Caskey, L. S., Sandahl, M. A., Hunter, D. M., Husted, C., Strunk, K. E., ... Earp, H. S. (2006). Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Molecular and cellular biology, 26(17), 6412-6424. https://doi.org/10.1128/MCB.01950-05

Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. / Muraoka-Cook, Rebecca S.; Caskey, Laura S.; Sandahl, Melissa A.; Hunter, Debra M.; Husted, Carty; Strunk, Karen E.; Sartor, Carolyn I.; Rearick, William A.; McCall, Wesley; Sgagias, Magdalene K.; Cowan, Kenneth H; Earp, H. Shelton.

In: Molecular and cellular biology, Vol. 26, No. 17, 01.09.2006, p. 6412-6424.

Research output: Contribution to journalArticle

Muraoka-Cook, RS, Caskey, LS, Sandahl, MA, Hunter, DM, Husted, C, Strunk, KE, Sartor, CI, Rearick, WA, McCall, W, Sgagias, MK, Cowan, KH & Earp, HS 2006, 'Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1', Molecular and cellular biology, vol. 26, no. 17, pp. 6412-6424. https://doi.org/10.1128/MCB.01950-05
Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE et al. Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. Molecular and cellular biology. 2006 Sep 1;26(17):6412-6424. https://doi.org/10.1128/MCB.01950-05
Muraoka-Cook, Rebecca S. ; Caskey, Laura S. ; Sandahl, Melissa A. ; Hunter, Debra M. ; Husted, Carty ; Strunk, Karen E. ; Sartor, Carolyn I. ; Rearick, William A. ; McCall, Wesley ; Sgagias, Magdalene K. ; Cowan, Kenneth H ; Earp, H. Shelton. / Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1. In: Molecular and cellular biology. 2006 ; Vol. 26, No. 17. pp. 6412-6424.
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