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Introduction
Breast cancer is the most common type of cancer and leading cause of cancer-related mortality in females with an estimated 1.7 million cases and 521,900 related fatalities in 2012 (1). Breast cancer is the most common type of cancer and was the leading cause of cancer mortality in women in 2008, and it is estimated that breast cancer will affect five million women worldwide over the subsequent decade (1). Over 60% of breast cancers are estrogen receptor (ER)-positive, and their development can be stimulated by estrogen and inhibited by ER antagonists, including tamoxifen.
Tamoxifen, broadly used in ER-positive breast cancer prevention and treatment, was approved as the first line anti-estrogen therapy in 1999 by the US Food and Drug Administration (2). Endocrine therapy with tamoxifen for five years has resulted in a 9.2% absolute reduction in mortality at 15 years, with a 34% reduction in the breast cancer mortality rate per year (3). However, the emergence of resistant cancer cells limits its therapeutic effectiveness (4,5). Thus, tamoxifen is typically administered in combination with other drugs, reducing the incidence of the development of drug resistance (6,7).
Previously, researchers have taken an increasing interest in combination therapy by associating anti-cancer herbal medicine with chemotherapeutic agents, and have demonstrated significant successes (8–10). Berberine, an isoquinoline plant alkaloid isolated from Coptidis rhizome, regulates multiple targets and may be a promising natural agent with chemotherapeutic potential based on its effect on the expression of various proteins (11–14). Berberine has previously been used to enhance cancer therapy sensitization and to assist chemo-therapy by modulating multiple pathways (15–17). These molecular targets of berberine are also involved in growth maintenance and resistance acquisition in tamoxifen-resistant breast cancer. Thus, a combination of berberine with tamoxifen may be an interesting option in the treatment of patients with ER-positive breast cancer.
The current study evaluated the individual and combined effects of berberine and tamoxifen in breast cancer MCF-7 and tamoxifen-resistant MCF-7/TAM cells. The results of the present study demonstrated that berberine does not abolish the anti-tumor effects of tamoxifen, and it induces cell G1 arrest, apoptosis, and significantly enhances the growth inhibition effect of tamoxifen in these cells. The mechanisms underlying these effects involve the regulation of important cell cycle and apoptosis-associated proteins.
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