Moores UCSD Cancer Center, University of California, San Diego, USA.
Differentiation. 2009 Dec;78(5):283-91. doi: 10.1016/j.diff.2009.07.007. Epub 2009 Aug 21.
We report the expression of melanocyte-related genes (MRG) in freshly resected, histopathologically confirmed, human breast cancer specimens and describe experiments illuminating similar observations on a variety of breast cancer cell lines including MDA-MB-435. This finding has implications for research on breast cancer, for clinical investigation of cancer patients presenting with metastases from occult primary tumors and for understanding aberrant differentiation in cancer cells. For example, higher expression of six MRG correlated inversely with propensity for metastatic spread in clones isolated from the human breast cancer cell line MDA-MB-435. Comparisons of MRG expression in cells growing in vitro with those seen in tumors generated by the same lines in vivo showed that the levels of activity of these genes are influenced by the surrounding environment. Also, silencing of expression of the melanocyte-related transcription factor MITF, by transduction of the non-metastatic clone NM2C5 with a construct expressing a specific anti-MITF shRNA, resulted in decreased production of 5 of the melanocyte-related proteins including TYRP1, Pmel 17, MART 1(Melan-A) and TYRP2, but no increase in metastatic capability. Hence MRG expression reproducibly ear-marked, but did not cause, metastatic incompetence. We also report cytogenetic and other data that conflict with the recent suggestion that MDA-MB-435 is of melanocytic origin and are more consistent with its original designation as being of mammary lineage. We conclude that detection of MRG expression profiles in freshly excised breast cancers and in cultured breast cancer cells reflects the operationally important clinical phenomenon of inappropriate gene expression in malignant neoplasms. Concomitantly, we suggest that the evidence we have obtained (i) collectively supports the continued widespread use of the MDA-MB-435 cell line in breast cancer and metastasis research and (ii) advances knowledge of the diversity of aberrant differentiation programs in malignant cells, which is valuable for making accurate diagnoses and treatment decisions in clinical oncology.
我们报告了黑色素细胞相关基因（MRG）在新鲜切除的、经组织病理学证实的人类乳腺癌标本中的表达，并描述了在多种乳腺癌细胞系（包括 MDA-MB-435）上进行的类似观察实验。这一发现对乳腺癌研究、对临床上隐匿性原发性肿瘤转移患者的癌症研究以及对癌细胞异常分化的理解具有重要意义。例如，在从人乳腺癌细胞系 MDA-MB-435 分离的克隆中，MRG 的表达较高与转移性扩散的倾向呈负相关。在体外生长的细胞与相同细胞系在体内生成的肿瘤中的 MRG 表达比较表明，这些基因的活性水平受周围环境的影响。此外，通过转导非转移性克隆 NM2C5 表达一种表达特异性抗 MITF shRNA 的构建体，沉默黑色素细胞相关转录因子 MITF 的表达，导致包括 TYRP1、Pmel 17、MART 1（Melan-A）和 TYRP2 在内的 5 种黑色素细胞相关蛋白的产生减少，但转移性能力没有增加。因此，MRG 的表达可重复性地标定，但不会导致转移性无能。我们还报告了细胞遗传学和其他与最近的建议相冲突的数据，该建议认为 MDA-MB-435 来源于黑色素细胞，而更符合其最初被指定为乳腺谱系的特征。我们得出结论，在新鲜切除的乳腺癌和培养的乳腺癌细胞中检测到 MRG 表达谱反映了恶性肿瘤中操作上重要的异常基因表达的临床现象。同时，我们建议我们获得的证据（i）共同支持 MDA-MB-435 细胞系在乳腺癌和转移研究中的广泛应用，（ii）推进了对恶性细胞中异常分化程序多样性的认识，这对于在临床肿瘤学中做出准确的诊断和治疗决策是有价值的。
