Department of Pathology, Josephine Nefkens Institute, Erasmus MC - University Medical Center Rotterdam, Be432, Erasmus MC. PO Box 2040, 3000 CA Rotterdam, The Netherlands.
Endocr Relat Cancer. 2010 Feb 18;17(1):215-30. doi: 10.1677/ERC-09-0062. Print 2010 Mar.
Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.
虽然内分泌治疗乳腺癌是有效的且是常规治疗手段，但在晚期疾病中，几乎不可避免地会出现耐药性。为了更深入地了解导致激素药物耐药的个别基因，我们进行了功能基因筛选，并随后评估了几种已确定的基因在雌激素受体阳性患者中对肿瘤侵袭性和他莫昔芬耐药性的临床相关性。用不同的逆转录病毒 cDNA 表达文库转导雌激素依赖性人乳腺癌细胞，并进行了各种抗雌激素药物的选择性培养。从总共 264 个耐药细胞克隆中，通过 PCR 回收了 132 个不同的基因。通过应用严格的选择标准，我们单独鉴定出了 15 个乳腺癌抗雌激素耐药（BCAR）基因，这些基因分别产生耐药性。BCAR 基因在不同的培养条件和抗雌激素药物中以不同的频率回收。对晚期疾病患者中 BCAR 基因（EIF1、FBXL10、HRAS、NRG1、PDGFRA、PDGFRB、RAD21 和 RAF1）与他莫昔芬治疗的关系进行分析表明，EIF1 和 PDGFRA mRNA 水平与临床获益和无进展生存期显著相关。此外，PDGFRA 和 HRAS mRNA 水平与未接受辅助全身治疗的淋巴结阴性患者的肿瘤侵袭性显著相关。总之，我们的功能基因筛选表明，BCAR 基因在抵抗不同抗雌激素药物方面的能力存在差异。基于几个 BCAR 基因的临床相关性，需要进一步研究以表征潜在机制，这可能最终导致开发新的治疗方法和对乳腺癌患者进行更个体化的管理。
