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
Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, 102 Mason Farm Road, Chapel Hill, NC 27599, USA.
Mol Cell Biol. 2006 Sep;26(17):6412-24. doi: 10.1128/MCB.01950-05.
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.
HER4在人类乳腺癌中的表达与良好预后相关。虽然这里调节蛋白抑制HER4阳性乳腺癌细胞的生长，但其作用机制尚不明确。我们证明，这里调节蛋白诱导的HER4活性抑制细胞增殖并延迟乳腺癌细胞的G(2)/M期进程。在研究G(2)/M期延迟的途径时，我们注意到这里调节蛋白以HER4依赖、HER2非依赖的方式增加BRCA1的表达。HER4对BRCA1的诱导独立于细胞周期。此外，在HER4阳性的人类乳腺癌标本中BRCA1表达升高。这里调节蛋白刺激c-Jun氨基末端激酶（JNK），对JNK的药理抑制损害了这里调节蛋白增强的BRCA1表达和有丝分裂延迟；对Erk1/2的抑制则没有这种作用。在人乳腺癌细胞系中用小干扰RNA敲低BRCA1会干扰HER4介导的有丝分裂延迟。利用一对同基因的小鼠乳腺上皮细胞（MECs）进一步研究了这里调节蛋白/HER4依赖的有丝分裂延迟，这对细胞来自携带位于BRCA1第11外显子两侧的纯合LoxP位点的小鼠，使得一个细胞系表达BRCA1，而另一个细胞系在Cre介导的切除后不表达。BRCA1阳性的MECs表现出这里调节蛋白依赖的有丝分裂延迟；然而，同基因的BRCA1阴性MECs则没有。这些结果表明，这里调节蛋白介导的HER4阳性乳腺癌细胞生长抑制需要BRCA1。
