Kaulfuss Silke, Herr Anna-Maria, Büchner Anja, Hemmerlein Bernhard, Günthert Andreas R, Burfeind Peter
Institute of Human Genetics, University Medical Center Göttingen, Germany.
Department of Pathology, University Medical Center Göttingen, Germany.
Int J Oncol. 2015 Jul;47(1):106-14. doi: 10.3892/ijo.2015.2988. Epub 2015 May 6.
Leupaxin belongs to the group of paxillin proteins and was reported to play a major role in the invasion and migration of prostate cancer cells. In the present study we were able to show by using a cDNA cancer profiling array that leupaxin is upregulated in breast and endometrial cancer, whereas downregulation of leupaxin was observed in lung cancer. In addition, immunohistochemical studies using a leupaxin-specific antibody on human breast cancer specimens (n=127) revealed that leupaxin is expressed mainly in invasive ductal carcinomas and ductal carcinoma in situ (40 and 49% respectively), and only in a minority of lobular mammary carcinomas. To further investigate the role of leupaxin in the progression of breast cancer the expression of leupaxin was analysed in six breast cancer cell lines. The estrogen receptor α (ERα)-positive HCC70 and the ERα-negative MDA-MB‑231 cells showed leupaxin expression on the RNA and protein level. Leupaxin localizes in these mammary carcinoma cells at focal adhesion sites and shuttles between membrane and nucleus via its LD4 motif as major nuclear export signal. Interaction partners of leupaxin in the nucleus represent the estrogen receptors ERα and ERβ. Both ERα and ERβ bind to the LIM domains of leupaxin via their AF-1/DNA binding domains. Furthermore, leupaxin is able to induce transcriptional activity of ERα independent of the presence of estradiol. The specific downregulation of leupaxin expression using siRNAs in mammary carcinoma cells resulted in reduced migratory capability and diminished invasiveness whereas no effect on proliferation was observed. Collectively, these results show that leupaxin has particular influence on the progression and invasion of breast cancer cells and may therefore represent an interesting candidate protein for diagnosis and therapeutic interventions.
白细胞盘蛋白属于桩蛋白家族，据报道其在前列腺癌细胞的侵袭和迁移中起主要作用。在本研究中，我们通过使用cDNA癌症分析阵列能够表明，白细胞盘蛋白在乳腺癌和子宫内膜癌中上调，而在肺癌中观察到白细胞盘蛋白下调。此外，使用白细胞盘蛋白特异性抗体对127例人乳腺癌标本进行免疫组织化学研究发现，白细胞盘蛋白主要表达于浸润性导管癌和原位导管癌（分别为40%和49%），仅在少数小叶乳腺癌中表达。为了进一步研究白细胞盘蛋白在乳腺癌进展中的作用，分析了六种乳腺癌细胞系中白细胞盘蛋白的表达。雌激素受体α（ERα）阳性的HCC70细胞和ERα阴性的MDA-MB-231细胞在RNA和蛋白质水平上均显示白细胞盘蛋白表达。白细胞盘蛋白在这些乳腺癌细胞中定位于粘着斑部位，并通过其作为主要核输出信号的LD4基序在细胞膜和细胞核之间穿梭。白细胞盘蛋白在细胞核中的相互作用伙伴为雌激素受体ERα和ERβ。ERα和ERβ均通过其AF-1/DNA结合结构域与白细胞盘蛋白的LIM结构域结合。此外，白细胞盘蛋白能够在不依赖雌二醇存在的情况下诱导ERα的转录活性。在乳腺癌细胞中使用小干扰RNA特异性下调白细胞盘蛋白表达导致迁移能力降低和侵袭性减弱，而未观察到对增殖的影响。总的来说，这些结果表明白细胞盘蛋白对乳腺癌细胞的进展和侵袭有特殊影响，因此可能是诊断和治疗干预的一个有趣候选蛋白。
