Abstract
CUL1 is an essential component of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. Our previous study has showed that CUL1 is positively associated with poor overall and disease-specific survival of breast cancer patients. Here, we further explored its roles in breast cancer metastasis. Our data showed that CUL1 significantly promoted breast cancer cell migration, invasion, tube formation in vitro, as well as angiogenesis and metastasis in vivo. In mechanism, the human gene expression profiling was used to determine global transcriptional changes in MDA-MB-231 cells, and we identified autocrine expression of the cytokines CXCL8 and IL11 as the target genes of CUL1 in breast cancer cell migration, invasion, metastasis, and angiogenesis. CUL1 regulated EZH2 expression to promote the production of cytokines, and finally significantly aggravating the breast cancer cell metastasis and angiogenesis through the PI3K–AKT–mTOR signaling pathway. Combined with the previous report about CUL1, we proposed that CUL1 may serve as a promising therapeutic target for breast cancer metastasis.
Highlights
Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide[1], and metastasis is responsible for 90% of deaths in breast cancer[2]
Reverse transcriptase polymerase chain reaction (RT-PCR) results revealed that the mRNA expression change of E-cadherin, fibronectin, vimentin, and N-cadherin in overexpressed MCF10A cells was coincident with the responsive proteins
Using intravenous tumor metastasis model and angiogenesis in vivo, we indicated that CUL1 knockdown significantly reduced the lung metastasis and angiogenesis
Summary
Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide[1], and metastasis is responsible for 90% of deaths in breast cancer[2]. Tumor metastasis involves sequentially well-characterized cascades of events, including cell proliferation, migration, invasion, adhesion, and angiogenesis[3]. Recent advances have provided provocative insights regarding the importance of cellbiological and molecular changes on metastasis[4]. To uncover the underlying molecular mechanism driving this process might contribute to the perfection of new metastatic paradigms and the development of future therapeutic interventions for metastasis. As a well-known scaffolding protein, CUL1 is an essential component of SCF E3 ubiquitin ligase complex. CUL1 regulates specific ubiquitination of some proteins and mediates diverse cellular processes, including early embryonic development and cell cycle control[5,6]. We have shown that the positive CUL1 staining in cancer tissues predicts poor prognosis of breast cancer patients, and subsequent
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