School of Medicine, University of Leeds, Leeds, United Kingdom.
Department of Breast Surgery, St. James's University Hospital, Leeds, United Kingdom.
Clin Breast Cancer. 2018 Dec;18(6):481-488. doi: 10.1016/j.clbc.2018.07.002. Epub 2018 Jul 6.
Neoadjuvant treatments for primary breast cancer are becoming more common; however, little is known about how these impact on response to subsequent adjuvant therapies. Conveniently, neoadjuvant therapy provides opportunities to consider this question, by studying therapy-induced expression changes using comparisons between pre- and posttreatment samples. These data are relatively lacking in the context of neoadjuvant endocrine therapy, as opposed to the more common neoadjuvant chemotherapy. Here, we investigate the relevance of expression of the xenobiotic transporter ABCG2/BCRP, a gene/protein associated with chemoresistance, in the context of neoadjuvant endocrine therapy and particularly with reference to subsequent chemotherapy treatment.
ABCG2/BCRP expression was assessed by immunohistochemistry or by expression arrays in matched patient samples pre- and post-neoadjuvant endocrine therapy. Cell culture was used to model the impact of endocrine therapy-induced changes in ABCG2/BCRP on subsequent chemotherapy response, using Western blots, quantitative polymerase chain reaction, survival assays, and cell cycle analyses.
ABCG2/BCRP was commonly and significantly upregulated in breast cancers after treatment with neoadjuvant endocrine therapy in 3 separate cohorts encompassing a total of 200 patients. Treatment with the endocrine therapeutic tamoxifen similarly induced ABCG2/BCRP upregulation in a relevant model cell line, the estrogen receptor-positive line T47D. Critically, this upregulation was associated with significantly increased chemoresistance to subsequent treatment with epirubicin, an anthracycline commonly used in breast cancer adjuvant chemotherapy.
Our data suggest that neoadjuvant endocrine therapy may induce poor responses to adjuvant chemotherapy, and therefore, that clinical outcomes following this treatment sequence warrant further study.
原发性乳腺癌的新辅助治疗越来越常见；然而，对于这些治疗如何影响后续辅助治疗的反应知之甚少。通过比较治疗前后的样本，新辅助治疗为研究治疗诱导的表达变化提供了机会，从而方便地研究这个问题。在新辅助内分泌治疗中，这种数据相对缺乏，而新辅助化疗则更为常见。在这里，我们研究了外排转运蛋白 ABCG2/BCRP 的表达在新辅助内分泌治疗中的相关性，特别是与随后的化疗治疗的相关性，ABCG2/BCRP 是一种与化疗耐药相关的基因/蛋白。
通过免疫组织化学或表达谱分析，在新辅助内分泌治疗前后的匹配患者样本中评估 ABCG2/BCRP 的表达。使用 Western blot、定量聚合酶链反应、生存分析和细胞周期分析，细胞培养用于模拟内分泌治疗诱导的 ABCG2/BCRP 变化对随后化疗反应的影响。
在 3 个共包含 200 例患者的独立队列中，新辅助内分泌治疗后，ABCG2/BCRP 在乳腺癌中普遍且显著上调。在相关的雌激素受体阳性细胞系 T47D 中，用内分泌治疗药物他莫昔芬治疗同样诱导了 ABCG2/BCRP 的上调。至关重要的是，这种上调与随后用表柔比星（一种常用于乳腺癌辅助化疗的蒽环类药物）治疗时的化学耐药性显著增加相关。
我们的数据表明，新辅助内分泌治疗可能导致对辅助化疗的反应不佳，因此，这种治疗序列后的临床结果值得进一步研究。
