Abstract
BackgroundThe β-catenin signaling is important in cell growth and differentiation and is frequently dysregulated in various cancers. The most well-known mechanism of endocrine resistance is cross-talk between the estrogen receptor (ER) and other growth factor signaling, such as phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathway. In the present study, we investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer.MethodsWe established tamoxifen-resistant (TamR) cell line via long-term exposure of MCF-7 breast cancer cells to gradually increasing concentrations of tamoxifen. The levels of protein expression and mRNA transcripts were determined using western blot analysis and real-time quantitative PCR. The transcriptional activity of β-catenin was measured using luciferase activity assay.ResultsTamR cells showed a mesenchymal phenotype, and exhibited a relatively decreased expression of ER and increased expression of human epidermal growth factor receptor 2 and the epidermal growth factor receptor. We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells. The expression and transcriptional activity of β-catenin were inhibited by β-catenin small-molecule inhibitor, ICG-001 or β-catenin siRNA. The viability of TamR cells, which showed no change after treatment with tamoxifen, was reduced by ICG-001 or β-catenin siRNA. The combination of ICG-001 and mTOR inhibitor, rapamycin, yielded an additive effect on the inhibition of viability in TamR cells.ConclusionThese results suggest that β-catenin plays a role in tamoxifen-resistant breast cancer, and the inhibition of β-catenin may be a potential target in tamoxifen-resistant breast cancer.
Highlights
Breast cancer is the second most common malignancy among women in South Korea
We confirmed that the expression and transcriptional activity of β-catenin were increased in TamR cells compared with control cells
Because the morphological changes which were shown in TamR cells, were associated with epithelial-mesenchymal transition (EMT) phenotype, we proceeded to assess the expression of EMT-related markers using western blotting
Summary
Breast cancer is the second most common malignancy among women in South Korea. It is a heterogeneous disease that can be classified into multiple subtypes with distinctive histological and biological features [1]. The most common subtype is the hormone receptor-positive breast cancer, about 70–75% of all breast cancers express the estrogen receptor (ER) or progesterone receptor (PR) [2]. Endocrine therapy to block ER activity is an important treatment for these patients [2]. Tamoxifen, which is a selective ER modulator, has been the mainstay of endocrine therapy for the management of ER-positive breast cancer. De novo (primary) or acquired (secondary) resistance to endocrine therapy remains an important clinical issue. Acquired resistance to endocrine therapy is common in clinical practice, and overcoming this resistance remains a crucial challenge in the treatment of ER-positive breast cancer. We investigated whether β-catenin could be a potential target to overcome endocrine resistance in breast cancer
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