Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1

被引:38
作者
Muraoka-Cook, Rebecca S.
Caskey, Laura S.
Sandahl, Melissa A.
Hunter, Debra M.
Husted, Carty
Strunk, Karen E.
Sartor, Carolyn I.
Rearick, William A., Jr.
McCall, Wesley
Sgagias, Magdalene K.
Cowan, Kenneth H.
Earp, H. Shelton, III
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Genet, Sch Med, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Radiat Oncol, Sch Med, Chapel Hill, NC 27599 USA
[4] Univ N Carolina, Dept Med, Sch Med, Chapel Hill, NC 27599 USA
[5] Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA
[6] Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA
关键词
D O I
10.1128/MCB.01950-05
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 G2/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 here gulin-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 BRCAI, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1positive 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.
引用
收藏
页码:6412 / 6424
页数:13
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