High Thioredoxin Expression Is Associated with Resistance to Docetaxel in Primary Breast Cancer

Abstract

Purpose: Thioredoxin overexpression is suggested to be associated with resistance to several chemotherapeutic agents in vitro. In the present study, it has been studied whether or not high thioredoxin expression is associated with resistance to docetaxel therapy in breast cancer patients. Patients and Methods: Sixty-three primary breast cancer patients were treated with docetaxel (60 mg/m 2 , q3w) for four cycles in the neoadjuvant setting. Expression of thioredoxin, estrogen receptor (ER), p53, BRCA-1, and Bcl-2 in tumor tissues obtained before docetaxel therapy was studied by immunohistochemistry (thioredoxin, p53, BRCA-1, and Bcl-2) and enzyme immunoassay (ER), and relationship of expression of these biomarkers with a pathologic response was investigated.Results: There was no significant correlation between the expression of p53, BRCA-1, or Bcl-2 and a response to docetaxel. However, tumors with high thioredoxin expression showed a significantly lower response rate (0%) than those with low thioredoxin expression (30.6%; P = 0.018) and ER-negative tumors showed a significantly higher response rate (32.4%) than ER-positive tumors (10.7%; P = 0.043).Thioredoxin expression significantly increased after docetaxel therapy (mean, 56.1%) as compared with that before docetaxel therapy (mean, 28.6%; P < 0.0001) but there was no significant association between the extent of increase in thioredoxin expression and response. Conclusion: High thioredoxin expression in prechemotherapy tumor samples, but not the increase in thioredoxin expression induced by docetaxel, is associated with resistance to docetaxel in breast cancer.Thioredoxin and ER might be clinically useful in the prediction of a response to docetaxel. Docetaxel, which belongs to taxanes, is one of the most powerful anticancer drugs for breast cancer, and an increasing number of breast cancer patients have been treated with docetaxel not only in the metastatic setting but also in the adjuvant setting, and more recently, in the neoadjuvant setting. The response rate of docetaxel, however, is f50% even in the first-line chemotherapy and it decreases to 20% to 30% in the second-or third-line chemotherapy (1 -3). Therefore, it is of vital importance to select the patients who are very likely to respond to docetaxel to eliminate the unnecessary treatment.

Chemotherapy Dosing Schedule Influences Drug Resistance Development in Ovarian Cancer

“…Stathmin1 stimulates microtubule depolymerization and interferes with taxane binding to b-tubulin subunits (26). This process is also obstructed by thioredoxin by interfering with the redox regulation of tubulin cysteine residues, which microtubule assembly depends on (29). It has been shown that thioredoxin expression increases in tumors after docetaxel treatment (29).…”

“…This process is also obstructed by thioredoxin by interfering with the redox regulation of tubulin cysteine residues, which microtubule assembly depends on (29). It has been shown that thioredoxin expression increases in tumors after docetaxel treatment (29). In chemoresistant (HeyA8-MDR) tumors, we found that intermittent 1Â/wk therapy leads to an upregulation of b-tubulinIII, stathmin1, and thioredoxin relative to controls and/or continuous chemotherapy and an upregulation of b-tubulinIII and stathmin1 was observed in chemosensitive (HeyA8) tumors.…”

“…Because docetaxel acts by stabilizing microtubules via binding to b-tubulin subunits, the abnormal expression of certain b-tubulin isotypes or proteins such as stathmin1 hinders drug binding to its target (23,26). The upregulation of genes such as actinin4, akt2, thioredoxin, and bcl2, which promote survival or inhibit apoptosis even in the presence of cytotoxic agents, has also been suggested to contribute to taxane or docetaxel resistance (27)(28)(29)(30). The expression of these genes was examined in xenografts extracted from severe combined immunodeficient (SCID) mice treated with continuous or intermittent (1Â/wk or 3Â/wk) docetaxel.…”

Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells

“…The thioredoxin system is often overexpressed in many cancer cells (5,6), and TrxR deficiency or transfection with dominant-negative mutant Trx leads to a retardation in tumor progression and metastasis (7)(8)(9). In addition, high Trx expression is associated with the resistance to tumor chemotherapy (10,11) and results in increased tumor angiogenesis (12). Supported by these observations, the thioredoxin system has been emerging as an important target for cancer treatment.…”

Upregulation of thioredoxin reductase 1 in human oral squamous cell carcinoma

“…The TrxR-Trx system is thought to have key functions in cancer cell proliferation. A number of reports have shown that the Trx-TrxR system has an important role in tumor growth and resistance to chemotherapeutic agents in many malignant neoplasms (22), i.e., prostate (23), pancreas (24), breast (25), non-small cell lung cancers (26), and malignant mesothelioma (27). Previous studies also reported that TrxR1 was one of the genes strongly associated with tumor proliferation in some cancers (23,28).…”