乳腺癌是目前发病率最高的女性恶性肿瘤之一，研究乳腺癌的耐药机制并研制治疗乳腺癌的有效药物具有重要的意义。当前有限的研究表明，乳腺癌组织在新辅助化疗前后基因表达谱发生改变；而肿瘤在化疗前后基因组是否存在差异有待进一步探讨。本项目前期的外显子组测序结果表明，化疗后乳腺癌组织较之化疗前产生了TEKT4基因的2个新的错义突变；在不同分子分型的乳腺癌中，有10% - 20%的个体化疗后新增这两种突变；过表达突变型的TEKT4可以降低微管的稳定性，从而增强乳腺癌细胞对紫杉醇的耐药性。我们计划以"TEKT-微管-含紫杉类化疗"为线索，在临床标本、动物模型、细胞培养及蛋白水平多种层面上，系统、深入地研究TEKT突变与乳腺癌适应性化疗抵抗的关系，初步阐释TEKT家族基因突变的生物学及临床意义，最终为临床上遴选耐紫杉类化疗的乳腺癌患者和采取个体化治疗提供线索。

Breast cancer is one of the most common cancers among women. It is of great importance to illustrate the drug-resistant mechanisms of breast cancer and identify resistant pathways that can be exploited for therapeutic selection. The changed gene-expression profiles of breast cancer under neoadjuvant chemotherapy have been described. However, the comparison of exomes and genomes of pre- and post-treatment samples remains elusive. We performed exome sequencing to examine the exomes (100-fold coverage) of one paired basal-like breast cancers (BLBC) samples (pre-treatment tumor biopsies and post-treatment tumors). Compared with pre-treatment biopsies, analysis of whole-exome sequence data identified and validated TEKT4 (tektin4) - a constitutive protein of microtubules in cilia, flagella, basal bodies and centrioles - as a significantly mutated gene in post-treatment tumors with a mutation frequency of 10% - 20% in an independent extension cohort of 84 paired samples of different molecular subtypes. TEKT4 mutations are biologically relevant, as ectopic expression of mutant TEKT4 deregulated microtubule stability and increased paclitaxel resistance of breast cancer cells both in vitro and in vivo. Taking advantage of patients' specimens, animal models and cell lines, we plan to investigate the relationship between TEKT mutation and adaptive drug resistance in the clue of "TEKT-microtubule-taxane chemotherapy". The identification of somatic mutations as biomarkers for pCR (pathologic complete remission) prediction and prognosis might help us optimize choice for cancer therapy and improve patients' survival.