Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.
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.
Muraoka-Cook
Rebecca S
RS
Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, 102 Mason Farm Road, Chapel Hill, NC 27599, USA.
Caskey
Laura S
LS
Sandahl
Melissa A
MA
Hunter
Debra M
DM
Husted
Carty
C
Strunk
Karen E
KE
Sartor
Carolyn I
CI
Rearick
William A
WA
McCall
Wesley
W
Sgagias
Magdalene K
MK
Cowan
Kenneth H
KH
Earp
H Shelton
HS
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005091:Exons / Q000235:genetics; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D020890:Neuregulin-1 / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D066246:ErbB Receptors; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020890:Neuregulin-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C587690:Erbb4 protein, mouse