Abstract
The extracellular matrix protein fibronectin (FN) facilitates tumorigenesis and the development of breast cancer. Inhibition of the FN-induced cellular response is a potential strategy for breast cancer treatment. In the present study, we investigated the effects of the flavonoid baicalein on FN-induced epithelial–mesenchymal transition (EMT) in MCF-10A breast epithelial cells and in a transgenic mouse MMTV-polyoma middle T antigen breast cancer model (MMTV-PyMT). Baicalein inhibited FN-induced migration, invasion, and F-actin remodeling. Baicalein also suppressed FN-induced downregulation of the epithelial markers E-cadherin and ZO-1 and upregulation of the mesenchymal markers N-cadherin, vimentin, and Snail. Further investigation revealed that calpain-2 was involved in baicalein suppression of FN-induced EMT. Baicalein significantly decreased FN-enhanced calpain-2 expression and activation by suppressing its plasma membrane localization, substrate cleavage, and degradation of its endogenous inhibitor calpastatin. Overexpression of calpain-2 in MCF-10A cells by gene transfection partially blocked the inhibitory effect of baicalein on FN-induced EMT changes. In addition, baicalein inhibited calpain-2 by decreasing FN-increased intracellular calcium ion levels and extracellular signal-regulated protein kinases activation. Baicalein significantly decreased tumor onset, growth, and pulmonary metastasis in a spontaneous breast cancer MMTV-PyMT mouse model. Baicalein also reduced the expression of FN, calpain-2, and vimentin, but increased E-cadherin expression in MMTV-PyMT mouse tumors. Overall, these results revealed that baicalein markedly inhibited FN-induced EMT by inhibiting calpain-2, thus providing novel insights into the pharmacological action and mechanism of baicalein. Baicalein may therefore possess therapeutic potential for the treatment of breast cancer though interfering with extracellular matrix–cancer cell interactions.
Highlights
Breast cancer is the most common cancer diagnosis in women worldwide[1]
Baicalein inhibits FN-induced migration, invasion, F-actin remodeling, and epithelial–mesenchymal transition (EMT)-related biomarker expression changes in MCF-10A cells As breast epithelial cell migration and invasion increase with increasing mesenchymal characteristics during breast cancer progression[27], we tested the effects of baicalein on FN-enhanced cell migration and invasion
The important role of EMT in promoting cancer progression and metastasis indicates that pharmacological interventions targeting this process may provide new therapeutic strategies for breast cancer[34]
Summary
Breast cancer is the most common cancer diagnosis in women worldwide[1]. The main adjuvant therapies after surgical treatment for breast cancer involve chemotherapy, hormonal therapy, and molecular targeted therapy, which depends on the patient’s hormone receptor or human epidermal growth factor (EGF) receptor 2 status[2]. breast cancer mortality rates have declined in line with improvements in early detection and treatment, Official journal of the Cell Death Differentiation AssociationChen et al Cell Death and Disease (2019)10:341 not all patients have benefited from these improvements, and it remains the second leading cause of cancer-related death among women in the United States[3]. FN transmits ECM signals to stimulate mammary epithelial cells to lose their growtharrested polarized characteristic, acquire tumor-like behavior, proliferate excessively, and eventually form a disturbed acinar structure in three-dimensional culture[10], whereas anti-FN antibodies induce T4-2 tumorigenic cells to form an organized polarized acinar identical to normal breast epithelial cells[11]. Therapeutic immunization using an antibody against extra domain-A of FN attenuated tumor burden and lung metastases in mouse mammary tumor virus polyoma virus middle T (MMTV-PyMT) mice[12]. These observations suggest that FN is a critical stimulator for breast tumor initiation and development. EMT is envisioned as a differentiation or morphogenetic process in embryogenesis, tissue repair, and remodeling, contributing to tumor progression[14]. FN alone or the assembly of FN fibrils, which contain the growth factor-binding domain and serve to localize transforming growth factor-β1 (TGF-β1) signaling, induces EMT in human mammary epithelial cells[17,18]
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