Abstract
Acquired resistance to doxorubicin in breast cancer is a serious therapeutic problem. In this study, we investigated whether Pseudomonas aeruginosa mannose‐sensitive hemagglutinin (PA‐MSHA) could inhibit the growth of doxorubicin‐resistant breast cancer cells. We found that the expressions of Nrf2 and p62 in breast cancer were higher than that in the corresponding adjacent normal tissues and benign breast epithelial cell. The expressions of Nrf2 and p62 in breast cancer doxorubicin‐resistant cells MCF‐7/ADR were higher than that in doxorubicin‐sensitive cells MCF‐7. Silencing of Nrf2 or p62 rendered breast cancer cells more susceptible to doxorubicin. We further demonstrated that PA‐MSHA inhibited growth and induced apoptosis of MCF‐7/ADR cells but not MCF‐7 cells. Subcutaneous administration of PA‐MSHA greatly inhibited the growth of xenograft tumors from MCF‐7/ADR cells in nude mice. In addition, PA‐MSHA could downregulate Nrf2 and p62 in vitro and in vivo. These results suggested that activation of Nrf2 and p62 was associated with doxorubicin resistance in breast cancer. PA‐MSHA could inhibit the growth of doxorubicin‐resistant MCF‐7/ADR cells and its potential mechanism might be due to the suppression of Nrf2/p62. It indicated the possibility of using PA‐MSHA in doxorubicin‐resistant breast cancer.
Highlights
Breast cancer is the most common cause of cancer- associated mortality among females worldwide
To investigate whether p62 is induced by nuclear factor erythroid-2-related factor 2 (Nrf2) activation, we introduced Nrf2 shRNA lentivirus into T47D and BT549 cells
Overexpression of p62 was able to disrupt the association between Nrf2 and Keap1, and lead to activation of Nrf2 [25]
Summary
Breast cancer is the most common cause of cancer- associated mortality among females worldwide. In China, it is the most frequently diagnosed malignant tumor and the sixth cause of cancer death in females, with an estimated 248,620 new cases and 60,473 deaths in 2011 [1]. Therapy for primary breast cancer usually involves surgery combined with radiotherapy, endocrine therapy, and/or chemotherapy. Doxorubicin (Dox) is a widely accepted chemotherapy drug used to suppress the growth and survival of human breast cancer cells. Intrinsic and acquired resistance to doxorubicin is common in breast cancer treatment and leads to subsequent treatment failures and recurrences [3]. Higher doses of available drugs may be ineffective. There is an urgent need to find a novel agent to conquer drug resistance in breast cancer
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