Abstract
MDR and tumor migration and invasion are still the main obstacles to effective breast cancer chemotherapies. Transgelin 2 has recently been shown to induce drug resistance, tumor migration, and invasion. The aim of this study was to determine the biological functions of Transgelin 2 and the mechanism underlying how Transgelin 2 induces paclitaxel (PTX) resistance and the migration and invasion of breast cancer. We detected that the protein level of Transgelin 2 was significantly upregulated in breast cancer tissues compared with adjacent nontumor tissues. A bioinformatics analysis indicated that Transgelin 2 was significantly related to clinicopathologic parameters and patient prognosis. Overexpression of Transgelin 2 enhanced the migration and invasion of human breast cancer cells and decreased the sensitivity of breast cancer cells to paclitaxel. Meanwhile, the tumorigenesis and metastasis of breast cancer cells were also enhanced by Transgelin 2 overexpression in vivo Moreover, Transgelin 2 overexpression activated the PI3K/Akt/GSK-3β pathway by increasing the phosphorylation levels of Akt and GSK-3β and decreasing the expression of PTEN. We also found that Transgelin 2 could directly interact with PTEN and was located upstream of PTEN. Furthermore, the PI3K/Akt pathway inhibitor MK-2206 reversed the resistance to paclitaxel and inhibited the migration and invasion of breast cancer cells. These findings indicate that Transgelin 2 promotes paclitaxel resistance and the migration and invasion of breast cancer by directly interacting with PTEN and activating the PI3K/Akt/GSK-3β pathway. Transgelin 2 may therefore be useful as a novel biomarker and therapeutic target for breast cancer.
Highlights
Breast cancer is the most common malignancy among women worldwide [1]
A subsequent multivariate logistic regression analysis found that the cancer type, estrogen receptor (ER) status, and histologic grade were independently associated with Transgelin 2 mRNA expression in breast cancers (Supplementary Table S3)
Transgelin 2 was reported to be correlated with lymph node metastasis, distant metastasis, and the TNM classification in colorectal cancer, and it may be useful as a new biomarker for predicting the progression and prognosis of colorectal cancer [24]
Summary
Breast cancer is the most common malignancy among women worldwide [1]. Treatment with a combination of chemotherapy and surgery has made remarkable progress in patients with breast cancer during the past few years, the recurrence and cancer death remain very high due to high frequency of metastasis and recurrence. Even though additional drugs were used, breast cancer cells generally gained MDR, causing tumor migration and invasion over time [2, 3]. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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