Abstract
Breast cancer has become the leading cause of cancer-related death among women. A large number of patients become resistant to drug chemotherapy. Paclitaxel (Taxol) is an effective chemotherapeutic agent used to treat cancer patients. Taxol has been widely used in human malignancies including breast cancer because it can stabilize microtubules resulting in cell death by causing an arrest during the G2/M phase of the cell cycle. Pro-apoptotic Bcl-2 antagonist killer 1 (Bak) plays an important role in Taxol-induced apoptosis in breast cancer. In our present study, we investigated the expression of the Bak protein and clinicopathological correlations in a large sample of breast cancer tissues by immunohistochemistry. We found that the percentage of high scores of Bak expression in breast cancer was significantly lower than that of the non-cancerous breast control tissue. In addition, lower Bak expression was positively associated with the clinical TNM stage of breast cancer with a significant decrease in overall survival compared with those with higher Bak expression especially in the Luminal and HER2 subtypes. Importantly, higher Bak expression predicted a favorable clinical outcome in the cases treated with Taxol indicated by a higher overall survival than that of patients with lower Bak expression especially in Luminal and HER2 subtypes. Furthermore, these results were confirmed in vitro since overexpression of Bak sensitized breast cancer cells to Taxol by inhibiting proliferation and promoting apoptosis; in contrast, downregulation of Bak through siRNA transfection inhibited Taxol induced-apoptosis. Therefore, our results demonstrate that Bak acts as a sensitive biomarker and favorable prognostic factor for Taxol treatment in breast cancer. The restoration of Bak expression would be therapeutically beneficial for Taxol resistant breast cancer patients.
Highlights
Drug resistance has become a major problem in cancer treatment [1]
We further investigated the association between the expression of the Bcl-2 antagonist killer 1 (Bak) protein and clinicopathological features of breast cancer including age, gender, tumor size, lymph node metastasis status, distant metastasis, and clinical tumor nodemetastasis (TNM) stage in a univariate chi-square test
Improvements have been made at the early stage of chemotherapy in breast cancer, a large proportion of patients are non-responsive to current treatment strategies due to drug resistance, such as Paclitaxel [14], highlighting the necessity to develop strategies to overcome or bypass drug resistance
Summary
Drug resistance has become a major problem in cancer treatment [1]. Paclitaxel (Taxol), a member of the taxane class of anti-neoplastic microtubule damaging agents widely used in human malignancies like breast cancer, can stabilize microtubules and subsequently cause cell death by arresting the cell cycle at G2/M [2]. Breast cancer cells frequently develop resistance to Taxol because of the evasion of apoptosis [3]. Even if a small proportion of the breast cancer patients are resistant to drug chemotherapy, it substantially affects a large number of patients [4]. Overcoming resistance to chemotherapy in breast cancer is one of the major issues in the management of breast cancer patients. It is necessary to identify useful biomarkers that distinguish sensitive patients and those resistant to drug treatment
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