PO.CL01.04 · 临床研究
Septin9亚型作为乳腺癌紫杉烷类反应的生物标志物
Septin9 isoforms as biomarkers of taxane response in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
包括紫杉烷类紫杉醇在内的微管靶向药物(MTA)被广泛用于乳腺癌的治疗。然而,目前尚无经临床验证的生物标志物来预测紫杉烷类反应。新出现的证据表明,septin(一类保守的GTP结合细胞骨架蛋白家族)是乳腺癌细胞在体外生长、迁移、侵袭及紫杉烷类反应的关键调控因子。值得注意的是,septin9(SEPT9)的各亚型具有相反的作用,其中SEPT9_i1促进迁移、上皮-间质转化和紫杉醇耐药,而SEPT9_i2则与致癌表型减弱相关,可能发挥保护性作用。我们检验了这一假设:乳腺肿瘤中septin9亚型的表达与乳腺癌患者对紫杉烷类化疗方案的反应相关,并在回顾性和前瞻性临床研究中进行了验证。在回顾性分析中,我们发现肿瘤表达最高水平SEPT9_i2 mRNA的紫杉烷类治疗患者转移后生存时间显著延长。值得注意的是,这一相关性仅在诊断为三阴性乳腺癌(TNBC)的女性中观察到,这类患者由于未联合使用靶向治疗药物,因此最为依赖对紫杉烷类的反应。在一项新辅助紫杉烷类反应的前瞻性研究中,对以紫杉烷类为基础的化疗方案达到病理完全缓解的女性,其肿瘤中SEPT9_i1 mRNA的表达显著低于非缓解者。此外,大多数在新辅助治疗中对紫杉烷类未完全缓解的肿瘤,在治疗后残余肿瘤中SEPT9_i1 mRNA表达升高。最后,我们验证了一种用于免疫组化的SEPT9_i1特异性抗体,且SEPT9_i1 mRNA与乳腺活检中的蛋白水平相关。实验室正在进行的实验正利用同基因细胞系和肿瘤模型阐明septin9亚型表达调控紫杉烷类化疗反应的机制。这项工作揭示了致癌亚型与抑癌亚型表达之间的相互关系,并为具有不良septin表达谱的肿瘤确定了替代化疗方案。
查看英文原文 English abstract
Microtubule-targeting agents (MTAs), including the taxane paclitaxel, are widely used for the treatment of breast cancer. However, there are no clinically validated biomarkers to predict taxane response. Emerging evidence implicates septins, a conserved family of GTP-binding cytoskeletal proteins, key regulators of growth, migration, invasion, and taxane response of breast cancer cells in vitro. Notably, isoforms of septin9 (SEPT9) have opposing roles with SEPT9_i1 promoting migration, epithelial-mesenchymal transition and paclitaxel resistance whereas SEPT9_i2 is associated with decreased oncogenic phenotypes and may serve a protective role. We tested the hypothesis that septin9 isoform expression in breast tumors correlates with the response of breast cancer patients to taxane chemotherapy regimens in both retrospective and prospective clinical studies. In a retrospective analysis we found a significant increase in post-metastatic survival time of taxane-treated patients whose tumors expressed the highest levels of SEPT9_i2 mRNA. Notably, this correlation was only observed in women diagnosed with triple-negative breast cancer (TNBC) that rely most heavily on response to taxanes as they are not co-administered with targeted therapeutics. In a prospective study of neoadjuvant taxane response, women with a complete pathological response to taxane-based chemotherapy regimens had significantly lower expression of SEPT9_i1 mRNA in their tumors than non-responders. Furthermore, majority of tumors that did not respond fully to taxanes in neoadjuvant settings had increased SEPT9_i1 mRNA expression in the residual tumor after treatment. Finally, we validated a SEPT9_i1 specific antibody for immunohistochemistry and SEPT9_i1 mRNA correlated with protein in breast biopsies. Ongoing experiments in the laboratory are elucidating the mechanism by which expression of septin9 isoforms regulates response to taxane chemotherapy using isogenic cell line and tumor models. This work is uncovering a reciprocal relationship between expression of oncogenic and tumor suppressive isoforms and identifying alternative chemotherapeutic options for treatment of tumors with unfavorable septin expression profiles.
利益披露 Disclosure
J. E. M. Bush, None..
J. Essif, None.