Rac1‐mediated sustained β4 integrin level develops reattachment ability of breast cancer cells after anchorage loss
| Autor: | Fumihiro Ishikawa, Masato Higurashi, Motoko Shibanuma, Kazunori Mori |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
rac1 GTP-Binding Protein
0301 basic medicine Cancer Research Programmed cell death Lung Neoplasms Integrin Breast Neoplasms RAC1 beta4 integrin Metastasis neoplasm metastasis 03 medical and health sciences breast cancer 0302 clinical medicine Breast cancer Cell Molecular and Stem Cell Biology Cell Line Tumor medicine Humans Cell adhesion biology Chemistry Integrin beta4 cell adhesion Original Articles General Medicine Adhesion Prognosis medicine.disease Gene Expression Regulation Neoplastic 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells biology.protein Cancer research Original Article Female Lysosomes Rac1 |
| Zdroj: | Cancer Science |
| ISSN: | 1349-7006 1347-9032 |
| DOI: | 10.1111/cas.14985 |
| Popis: | Previously, we reported that non‐apoptotic cell death was induced in non‐malignant mammary epithelial cells (HMECs) upon loss of anchorage during 48 h incubation in suspension. In this study, we examined HMECs in suspension at an earlier time point and found that most of them lost attachment ability to substrata when replated, although >80% were alive. This suggested that HMECs lost reattachment ability (RA) prior to cell death upon detachment. Concomitant with the loss of RA, a decrease in the levels of β1 and β4 integrin was observed. In sharp contrast, breast cancer cells retained integrin levels, reattached to substrata, and formed colonies after exposure to anchorage loss as efficiently as those maintained under adherent conditions. Such RA of cancer cells is essential for the metastatic process, especially for establishing adhesion contact with ECM in the secondary organ after systemic circulation. Further analysis suggested that sustained levels of β4 integrin, which was mediated by Rac1, was critical for RA after anchorage loss and lung metastasis of breast cancer cells. In the cancer cells, persistent Rac1 activity enhanced escape of β4 integrin from lysosomal degradation depending on actin‐related protein 2/3 and TBC1D2, a GTPase‐activating protein of Rab7 GTPase. Notably, simultaneous high expression of ITGB4 and RAC1 was associated with poor prognosis in patients with breast cancer. Therefore, β4 integrin and Rac1 are attractive therapeutic targets to eliminate RA in cancer cells, thereby preventing the initial step of colonization at the secondary organ during metastasis. Anchorage‐independent reattachment ability (RA) of cells is as important as anchorage‐independent survival or growth for cancer metastasis. The Rac1/beta4 integrin axis has emerged as a critical mediator of RA of breast cancer cells in this study. Notably, simultaneous high expression of RAC1 and ITGB4 was associated with poor prognosis in patients with breast cancer. |
| Databáze: | OpenAIRE |
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