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The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis
Yingchun Liang1, Xiaojie Xu1, Tao Wang2
1Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Collaborative Innovation Center for Cancer Medicine, Beijing, China.
Abstract:
Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3'-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer.
Insights
Epidermal growth factor receptor (EGFR) drives breast cancer growth and metastasis by suppressing microRNA-338-3p (miR-338-3p) and activating EYA2. This miR-338-3p/EYA2 pathway offers new therapeutic targets for metastatic breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) dysregulation is a key driver of cancer progression, including breast cancer.
- Understanding downstream effectors of EGFR is crucial for developing targeted therapies.
- The role of microRNAs and specific oncoproteins in EGFR-mediated metastasis requires further elucidation.
Purpose of the Study:
- To investigate the role of the miR-338-3p/EYA2 pathway in EGFR-driven breast cancer growth and metastasis.
- To elucidate the molecular mechanisms by which EGFR influences miR-338-3p and EYA2 expression.
- To evaluate the potential of targeting this axis for therapeutic intervention in metastatic breast cancer.
Main Methods:
- Investigated EGFR's effect on miR-338-3p and EYA2 expression in vitro and in vivo.
- Utilized luciferase reporter assays to confirm direct binding of miR-338-3p to EYA2 3'-UTR.
- Employed an allograft tumor mouse model to assess tumor growth and metastasis.
- Correlated expression levels of EGFR, miR-338-3p, and EYA2 with clinical data from breast cancer patients.
Main Results:
- EGFR promotes breast tumor growth and metastasis by downregulating miR-338-3p and upregulating EYA2.
- EGFR represses miR-338-3p via HIF1α, and miR-338-3p directly inhibits EYA2.
- EGFR-induced activation of the miR-338-3p/EYA2 pathway enhances cancer cell growth, EMT, migration, invasion, and lung metastasis.
- Clinical data show inverse correlation between miR-338-3p and EGFR/EYA2, and positive association between EGFR and EYA2, with miR-338-3p/EYA2 predicting lung metastasis.
Conclusions:
- The miR-338-3p/EYA2 axis is a critical mediator of EGFR-driven breast cancer progression and lung metastasis.
- Targeting EGFR, miR-338-3p, or EYA2, individually or in combination, represents a promising therapeutic strategy for metastatic breast cancer.
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