Abstract
Invasion, metastasis and chemoresistance are leading causes of death in breast cancer patients. A vital change of epithelial cells, epithelial–mesenchymal transition (EMT), is involved in these processes. Unfortunately, the molecular mechanisms controlling EMT remain to be elucidated. Our previous studies have shown that ectopic N3ICD expression inhibits EMT in MDA-MB-231, a triple-negative breast cancer (TNBC) epithelial cell line. To decipher the mechanism, we performed in-depth studies. Specifically, we found that overexpressing N3ICD transcriptionally upregulated the expression of Kibra, an upstream member of the Hippo pathway. Correspondingly, we also observed that phosphorylated Hippo pathway core kinases, including Lats1/2 and MST1/2, were increased and decreased by overexpressing and knocking down Notch3, respectively. Furthermore, we found that the oncogenic transcriptional coactivator yes-associated protein (YAP), which is negatively regulated by the Hippo pathway, was inhibited by overexpressing N3ICD in breast cancer epithelial cells. The ability of Kibra to inhibit EMT has been previously reported. We thus speculated that Notch3 inhibition of EMT is mediated by upregulated Kibra. To verify this hypothesis, a rescue experiment was performed. Evidently, the ability of Notch3 to inhibit EMT can be countered by knocking down Kibra expression. These data suggest that Notch3 inhibits EMT by activating the Hippo/YAP pathway by upregulating Kibra in breast cancer epithelial cells, and Kibra may be a downstream effector of Notch3. These findings deepen our understanding of EMT in both development and disease, and will undoubtedly help to provide new therapeutic strategies for interfering with cancer invasion and metastasis, especially for TNBC.
Highlights
Breast cancer affects the lives of millions, and has become a major health problem in China and worldwide
We present solid evidence that Notch[3] can act as a tumor suppressor in breast cancer epithelial cells, that the loss of Notch[3] is an important feature of triple-negative breast cancer (TNBC), and that Notch[3] inhibits epithelial–mesenchymal transition (EMT) by activating the Hippo/yes-associated protein (YAP) pathway mediated by Kibra in breast cancer
We determined relative Notch[3] and E-cadherin expression levels via western blotting in five human breast cancer cell lines including MCF-7, T47D, SKBR3, MDA-MB-231(two strains stored in different laboratory) and BT549, of which MCF-7 and T47D are characterized as ER-/PgR-positive luminal mammary carcinoma, MDA-MB-231 and BT549 are characterized as triple-negative/ basal-B mammary carcinoma (TNBC), and SKBR3 is a human breast cancer cell line that overexpresses the Her[2] (Neu/ErbB-2) gene product
Summary
Breast cancer affects the lives of millions, and has become a major health problem in China and worldwide. Many scientific advancements and a great deal of progress have been made in breast cancer research such that the chances of disease-free survival for breast cancer survivors has increased tremendously over the last few decades, most patients with breast cancer cannot escape eventual recurrence, metastasis and chemoresistance, because breast cancer is a heterogeneous disease characterized by different molecular drivers. The epithelial–mesenchymal transition (EMT) is a critical biological process during embryonic development that endows epithelial malignant tumor with the increased abilities of motility and invasiveness, chemoresistance and radioresistance.[1] It is considered the probable first key step in the complex processes of chemoresistance, local recurrence and distant metastasis.[2,3,4] Over the last few decades, the mechanisms of EMT initiation and progression have been widely studied, and a number of hypotheses have been proposed[5,6] including multiple oncogenic events, important signaling pathways, cancer stem cells and miRNA. A comprehensive understanding of the molecular mechanisms and discovering ‘driver genes’ for breast cancer recurrence and metastasis are vital for recently proposed precision medicine
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