van Agthoven T, Sieuwerts A M, Veldscholte J, Meijer-van Gelder M E, Smid M, Brinkman A, den Dekker A T, Leroy I M, van Ijcken W F J, Sleijfer S, Foekens J A, Dorssers L C J
Department of Pathology, Erasmus MC-University Medical Center Rotterdam, Rotterdam 3000 CA, The Netherlands.
Br J Cancer. 2009 Dec 1;101(11):1824-32. doi: 10.1038/sj.bjc.6605423. Epub 2009 Nov 10.
Endocrine therapies of breast cancer are effective but ultimately fail because of the development of treatment resistance. We have previously revealed several genes leading to tamoxifen resistance in vitro by retroviral insertion mutagenesis. To understand the manner in which these genes yield tamoxifen resistance, their effects on global gene expression were studied and those genes resulting in a distinct gene expression profile were further investigated for their clinical relevance.
Gene expression profiles of 69 human breast cancer cell lines that were made tamoxifen resistant through retroviral insertion mutagenesis were obtained using oligonucleotide arrays and analysed with bioinformatic tools. mRNA levels of NCOR2 and CITED2 in oestrogen receptor-positive breast tumours were determined by quantitative RT-PCR. mRNA levels were evaluated for association with metastasis-free survival (MFS) in 620 patients with lymph node-negative primary breast cancer who did not receive systemic adjuvant therapy, and with clinical benefit in 296 patients receiving tamoxifen therapy for recurrent breast cancer.
mRNA expression profiles of most tamoxifen-resistant cell lines were strikingly similar, except for the subgroups of cell lines in which NCOR2 or CITED2 were targeted by the retrovirus. Both NCOR2 and CITED2 mRNA levels were associated with MFS, that is, tumour aggressiveness, independently of traditional prognostic factors. In addition, high CITED2 mRNA levels were predictive for a clinical benefit from first-line tamoxifen treatment in patients with advanced disease.
Most retrovirally targeted genes yielding tamoxifen resistance in our cell lines do not impose a distinctive expression profile, suggesting that their causative role in cell growth may be accomplished by post-transcriptional processes. The associations of NCOR2 and CITED2 with outcome in oestrogen receptor-positive breast cancer patients underscore the clinical relevance of functional genetic screens to better understand disease progression, which may ultimately lead to the development of improved treatment options.
乳腺癌的内分泌治疗有效，但最终会因治疗耐药性的出现而失败。我们之前通过逆转录病毒插入诱变在体外揭示了几个导致他莫昔芬耐药的基因。为了解这些基因产生他莫昔芬耐药性的方式，研究了它们对整体基因表达的影响，并进一步研究了那些导致独特基因表达谱的基因的临床相关性。
使用寡核苷酸阵列获得了69个人类乳腺癌细胞系的基因表达谱，这些细胞系通过逆转录病毒插入诱变产生了他莫昔芬耐药性，并使用生物信息学工具进行分析。通过定量逆转录聚合酶链反应测定雌激素受体阳性乳腺肿瘤中NCOR2和CITED2的mRNA水平。评估了620例未接受全身辅助治疗的淋巴结阴性原发性乳腺癌患者的mRNA水平与无转移生存期（MFS）的相关性，以及296例接受他莫昔芬治疗复发性乳腺癌患者的mRNA水平与临床获益的相关性。
除了逆转录病毒靶向NCOR2或CITED2的细胞系亚组外，大多数他莫昔芬耐药细胞系的mRNA表达谱惊人地相似。NCOR2和CITED2的mRNA水平均与MFS相关，即与肿瘤侵袭性相关，独立于传统预后因素。此外，高CITED2 mRNA水平可预测晚期疾病患者一线他莫昔芬治疗的临床获益。
在我们的细胞系中，大多数导致他莫昔芬耐药的逆转录病毒靶向基因并未呈现出独特的表达谱，这表明它们在细胞生长中的致病作用可能是通过转录后过程实现的。NCOR2和CITED2与雌激素受体阳性乳腺癌患者预后的相关性强调了功能基因筛选对于更好地理解疾病进展的临床相关性，这最终可能导致开发出更好的治疗方案。
