NF-KB activation in human breast cancer specimens and its role in cell proliferation and apoptosis
NF-KB activation in human breast cancer specimens and its role in cell proliferation and apoptosis
复制标题
DOI：
10.1073/pnas.0403621101
复制
发表时间：
2004-07-06
影响因子：
11.1
通讯作者：
Iglehart, JD
中科院分区：
文献类型：
--
作者：
Biswas, DK;Shi, Q;Iglehart, JD
雌激素受体阴性（er阴性）乳腺癌缺乏分子靶点是治疗的主要障碍。我们研究了NF-kappaB在人乳腺肿瘤和乳腺癌细胞系中的活化。活化的NF-kappaB主要在er阴性和er阳性乳腺肿瘤中检测到，并且主要在er阴性和erbb2阳性肿瘤中检测到（86%）。这些体内结果表明，活化的NF-kappaB与人类乳腺肿瘤的一个亚组存在关联，并且与先前报道的使用类似类别的人类乳腺癌细胞系的体外观察结果一致。发现这种联系表明了功能和生物学意义。免疫荧光显示，在er阴性/ erbb2阳性肿瘤样本的细胞角蛋白19 （CK19）阳性上皮细胞中，核p65（活性NF-kappaB复合物的一个组成部分）增加。相比之下，核NF-kappaB主要在er阴性和erbb2阴性肿瘤的基质中检测到，这表明在这类乳腺癌中，活化的NF-kappaB在上皮细胞和基质细胞之间的细胞间信号传导中起作用。为了阐明活化NF-kappaB的作用，我们使用er阴性和erbb2阳性的人乳腺肿瘤细胞系（SKBr3）。多肽heregulin β 1刺激了SKBr3细胞中NF-kappaB的激活，而抗erbb2抗体herceptin则抑制了NF-kappaB的激活。NF-kappaB必需调节因子（NEMO）结合域（NBD）肽是ikappab激酶（IKK）的选择性抑制剂，可阻断heregulin介导的NF-kappaB活化和细胞增殖，同时仅在增殖细胞中诱导细胞凋亡，而非静止细胞。这些结果证实了某些乳腺癌细胞依赖NF-kappaB进行异常细胞增殖并同时避免细胞凋亡的假设，从而暗示活化的NF-kappaB是er阴性乳腺癌不同亚类的治疗靶点。
Lack of molecular targets in estrogen receptor-negative (ER-negative) breast cancer is a major therapeutic hurdle. We studied NF-kappaB activation in human breast tumors and in carcinoma cell lines. Activated NF-kappaB was detected predominantly in ER-negative vs. ER-positive breast tumors and mostly in ER-negative and ErbB2-positive tumors (86%). These in vivo results demonstrate association of activated NF-kappaB with a subgroup of human breast tumors and are consistent with previously reported in vitro observations using similar classes of human breast cancer cell lines. Finding such an association suggested functional and biological significance. Immunofluorescence demonstrated increased nuclear p65, a component of the active NF-kappaB complex, in cytokeratin 19 (CK19)-positive epithelial cells of ER-negative/ErbB2-positive tumor samples. In contrast, nuclear NF-kappaB was detected mostly in stroma of ER-negative and ErbB2-negative tumors, suggesting a role of activated NF-kappaB in intercellular signaling between epithelial and stromal cells in this type of breast cancers. To elucidate roles of activated NF-kappaB, we used an ER-negative and ErbB2-positive human breast tumor cell line (SKBr3). The polypeptide heregulin beta1 stimulated, and herceptin, the anti-ErbB2 antibody, inhibited, NF-kappaB activation in SKBr3 cells. The NF-kappaB essential modulator (NEMO)-binding domain (NBD) peptide, an established selective inhibitor of IkappaB-kinase (IKK), blocked heregulin-mediated activation of NF-kappaB and cell proliferation, and simultaneously induced apoptosis only in proliferating and not resting cells. These results substantiate the hypothesis that certain breast cancer cells rely on NF-kappaB for aberrant cell proliferation and simultaneously avoid apoptosis, thus implicating activated NF-kappaB as a therapeutic target for distinctive subclasses of ER-negative breast cancers.