Role of cytoplasmic localization of maspin in promoting cell invasion in breast cancer with aggressive phenotype

Tomohiko Sakabe,Makoto Wakahara,Yoshihisa Umekita,Goshi Shiota

doi:10.1038/s41598-021-90887-z

Tomohiko Sakabe, Makoto Wakahara + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-90887-z

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Journal: Scientific Reports	Publication Date: May 31, 2021
Citations: 8	License type: open-access

Affiliation: Tottori University

Abstract

Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is downregulated during carcinogenesis and breast cancer progression. While the nuclear localization of maspin is essential for tumor suppression, we previously reported that the cytoplasmic localization of maspin was significantly correlated with poor prognosis in breast cancer patients. To understand the mechanisms that underlie oncogenic role of cytoplasmic maspin, we studied its biological function in breast cancer cell lines. Subcellular localization of maspin in MDA-MB-231 breast cancer cells was mainly detected in the cytoplasm, whereas in MCF10A mammary epithelial cells, maspin was present in both cytoplasm and nucleus. In MDA-MB-231 cells, maspin overexpression promoted cell proliferation and cell invasion, whereas maspin downregulation resulted in the opposite effect. Further, we observed that SRGN protein levels were increased in MDA-MB-231 cells stably overexpressing maspin. Finally, maspin overexpression in MDA-MB-231 cells resulted in the N-cadherin and epithelial mesenchymal transition (EMT)-related transcription factors upregulation, and TGFβ signaling pathway activation. These results suggested that cytoplasmic maspin enhances the invasive and metastatic potential in breast cancer cells with aggressive phenotype by inducing EMT via SRGN/TGFβ axis. This study demonstrated a novel biological function of cytoplasmic maspin in progression of breast cancer cells with an aggressive phenotype.

Highlights

Mammary serine protease inhibitor is a tumor suppressor gene that is downregulated during carcinogenesis and breast cancer progression
We reported that cytoplasmic localization of maspin was related to the poor prognosis in breast cancer patients[21]
Maspin protein was localized to both nucleus and cytoplasm in MCF10A cells, whereas maspin protein signal was mostly detected in the cytoplasm of MCF-7 and MDA-MB-231 cells (Fig. 1E,F, Supplementary Fig. S1)

Summary

Introduction

Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is downregulated during carcinogenesis and breast cancer progression. Maspin overexpression in MDA-MB-231 cells resulted in the N-cadherin and epithelial mesenchymal transition (EMT)-related transcription factors upregulation, and TGFβ signaling pathway activation. These results suggested that cytoplasmic maspin enhances the invasive and metastatic potential in breast cancer cells with aggressive phenotype by inducing EMT via SRGN/TGFβ axis. Goulet et al reported that nuclear localization of maspin is indispensable to its tumor suppressive function[20] Based on these findings, we hypothesized that maspin has different functions in carcinogenesis and tumor progression, which depend on its subcellular localization, and that cytoplasmic maspin might positively contribute to the acquisition of malignant and aggressive phenotype in cancer cells. No studies have examined the oncogenic role of maspin in breast cancer cells, ; we investigated the biological function of cytoplasmic maspin in breast cancer cells

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