Role of KCNMA1 gene in breast cancer invasion and metastasis to brain.
Role of KCNMA1 gene in breast cancer invasion and metastasis to brain.
复制标题
DOI：
10.1186/1471-2407-9-258
复制
发表时间：
2009-07-29
期刊：
影响因子：
3.8
通讯作者：
Ningaraj NS
中科院分区：
文献类型：
--
作者：
Khaitan D;Sankpal UT;Weksler B;Meister EA;Romero IA;Couraud PO;Ningaraj NS
乳腺肿瘤转移至脑部的患者预后极差。鉴别转移过程的预后分子标记对于设计减少转移发生的治疗方式至关重要。尽管大电导钙和电压激活钾通道（BKCa）在大多数人体器官中普遍存在，但在乳腺癌细胞中却显著上调。在这项研究中，我们研究了编码BKCa通道成孔α-亚基的KCNMA1基因在乳腺癌转移和侵袭中的作用。我们采用Global外显子阵列研究KCNMA1在转移性乳腺癌脑中的表达，比较其在原发性乳腺癌和其他器官转移性乳腺癌中的表达，并通过RT-PCR验证结果。采用免疫组化方法研究BKCa通道蛋白在原发性、转移性乳腺癌组织和乳腺癌细胞系中的表达和定位。我们对已建立的正常乳腺细胞（MCF-10A）、非转移性乳腺癌（MCF-7）、非脑转移性乳腺癌细胞（MDA-MB-231）和脑特异性转移性乳腺癌细胞（MDA-MB-361）进行了基质侵袭、跨内皮迁移和膜电位测定，以研究BKCa通道抑制是否通过siRNA敲低KCNMA1和Iberiotoxin （IBTX）的生化抑制来减弱乳腺肿瘤的侵袭和转移。Global外显子阵列和RT-PCR显示，与其他器官的转移性乳腺癌相比，KCNMA1在脑转移性乳腺癌中的表达更高。我们的研究结果清楚地表明，转移性乳腺癌细胞表现出增加的BKCa通道活性，导致更大的侵袭性和跨内皮迁移，这两种情况都可以通过阻断KCNMA1来减弱。确定BKCa通道在脑转移乳腺癌中的相对丰度及其在脑转移中的作用机制，将为识别和区分转移风险高的低级别乳腺肿瘤和转移风险低的乳腺肿瘤提供一个独特的机会。这种区别反过来又允许适当和有效地应用有效的治疗方法，同时使转移风险低的患者免受化疗毒副作用的影响。
The prognosis for patients with breast tumor metastases to brain is extremely poor. Identification of prognostic molecular markers of the metastatic process is critical for designing therapeutic modalities for reducing the occurrence of metastasis. Although ubiquitously present in most human organs, large-conductance calcium- and voltage-activated potassium channel (BKCa) channels are significantly upregulated in breast cancer cells. In this study we investigated the role of KCNMA1 gene that encodes for the pore-forming α-subunit of BKCa channels in breast cancer metastasis and invasion. We performed Global exon array to study the expression of KCNMA1 in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of BKCa channel protein in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells (MCF-10A), non-metastatic breast cancer (MCF-7), non-brain metastatic breast cancer cells (MDA-MB-231), and brain-specific metastatic breast cancer cells (MDA-MB-361) to study whether BKCa channel inhibition attenuates breast tumor invasion and metastasis using KCNMA1 knockdown with siRNA and biochemical inhibition with Iberiotoxin (IBTX). The Global exon array and RT-PCR showed higher KCNMA1 expression in metastatic breast cancer in brain compared to metastatic breast cancers in other organs. Our results clearly show that metastatic breast cancer cells exhibit increased BKCa channel activity, leading to greater invasiveness and transendothelial migration, both of which could be attenuated by blocking KCNMA1. Determining the relative abundance of BKCa channel expression in breast cancer metastatic to brain and the mechanism of its action in brain metastasis will provide a unique opportunity to identify and differentiate between low grade breast tumors that are at high risk for metastasis from those at low risk for metastasis. This distinction would in turn allow for the appropriate and efficient application of effective treatments while sparing patients with low risk for metastasis from the toxic side effects of chemotherapy.
登录
查看更多内容
影响因子：
--
作者：
Man S;Ubogu EE;Williams KA;Tucky B;Callahan MK;Ransohoff RM
通讯作者：
Ransohoff RM
影响因子：
4.8
作者：
Weksler, BB;Subileau, EA;Couraud, PO
通讯作者：
Couraud, PO
影响因子：
8.4
作者：
Shmueli, E;Wigler, N;Inbar, M
通讯作者：
Inbar, M
影响因子：
50.3
作者：
Mu, D;Chen, LY;Powers, S
通讯作者：
Powers, S
影响因子：
50.3
作者：
Kang, YB;Siegel, PM;Massagué, J
通讯作者：
Massagué, J