Enriched variations in TEKT4 and breast cancer resistance to paclitaxel.
Among chemotherapeutic agents, paclitaxel has shown great efficacy against breast cancer. Prediction of paclitaxel response may improve patient outcomes. Here we show, using exome sequencing, that in comparison with pre-treatment biopsies, two TEKT4 germline variations are enriched in post-treatment tumours. We find TEKT4 variations in ~ 10% of an independent cohort of 84 pairs of samples. Tektin4 (encoded by TEKT4) associates closely with tubulin in doublet microtubules and helps stabilize these structures. These two TEKT4 germline variations in a high cis linkage are biologically relevant, as the ectopic expression of variant TEKT4 deregulates the microtubule stability, antagonizes the paclitaxel-induced stabilizing effect of microtubules and increases paclitaxel resistance. Furthermore, TEKT4 germline variations are associated with reduced disease-free survival and overall survival compared with wild-type TEKT4 in patients undergoing paclitaxel-based chemotherapy. Taken together, we reveal a potential mechanism of resistance to paclitaxel through the acquisition of germline variations in breast cancer.
1] Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China [2].
Yi-Zhou
YZ
Jiang
1] Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China [2].
Ke-Da
KD
Yu
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Wen-Ting
WT
Peng
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Gen-Hong
GH
Di
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Jiong
J
Wu
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Guang-Yu
GY
Liu
Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Zhi-Ming
ZM
Shao
D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008868:Microtubule Proteins / Q000235:genetics*; D008870:Microtubules / Q000378:metabolism*; D008875:Middle Aged; D017239:Paclitaxel / Q000627:therapeutic use*; D011379:Prognosis
D000972:Antineoplastic Agents, Phytogenic; D008868:Microtubule Proteins; C044103:tektins; D017239:Paclitaxel