Open AccessHeregulin-Dependent Delay in Mitotic Progression Requires HER4 and BRCA1
Author(s) -
Rebecca S. Muraoka-Cook,
Laura S. Caskey,
Melissa Sandahl,
Debra Hunter,
Carty Husted,
Karen E. Strunk,
Carolyn I. Sartor,
William A. Rearick,
Wesley McCall,
Magdalene K. Sgagias,
Kenneth H. Cowan,
H. Shelton Earp
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01950-05
Subject(s) - neuregulin , biology , cancer research , gene knockdown , mitosis , small interfering rna , neuregulin 1 , cell growth , cell culture , microbiology and biotechnology , transfection , signal transduction , genetics
HER4 expression in human breast cancers correlates with a positiveprognosis. While heregulin inhibits the growth of HER4-positive breastcancer cells, it does so by undefined mechanisms. We demonstrate thatheregulin-induced HER4 activity inhibits cell proliferation and delaysG2 /M progression of breast cancer cells. While investigatingpathways of G2 /M delay, we noted that heregulin increasedthe 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 breastcancer specimens. Heregulin stimulated c-Jun N-terminalkinase (JNK), and pharmacologic inhibition of JNK impairedheregulin-enhanced expression of BRCA1 and mitotic delay;inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interferingRNA in a human breast cancer cell line interfered with HER4-mediatedmitotic delay. Heregulin/HER4-dependent mitotic delay was examinedfurther with an isogenic pair of mouse mammary epithelial cells (MECs)derived from mice harboring homozygous LoxP sites flanking exon 11 ofBRCA1, such that one cell line expressed BRCA1 while the other cellline, after Cre-mediated excision, did not. BRCA1-positive MECsdisplayed heregulin-dependent mitotic delay; however, the isogenicBRCA1-negative MECs did not. These results suggest thatheregulin-mediated growth inhibition in HER4-postive breast cancercells requiresBRCA1.