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CIP4 promotes metastasis in triple-negative breast cancer and is associated with poor patient prognosis
Otto L D Cerqueira1, Peter Truesdell2, Tomas Baldassarre2
1Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil.
Abstract:
Signaling via epidermal growth factor receptor (EGFR) and Src kinase pathways promote triple-negative breast cancer (TNBC) cell invasion and tumor metastasis. Here, we address the role of Cdc42-interacting protein-4 (CIP4) in TNBC metastasis in vivo, and profile CIP4 expression in human breast cancer patients. In human TNBC cells, CIP4 knock-down (KD) led to less sustained activation of Erk kinase and impaired cell motility compared to control cells. This correlated with significant defects in 3D invasion of surrounding extracellular matrix by CIP4 KD TNBC cells when grown as spheroid colonies. In mammary orthotopic xenograft assays using both human TNBC cells (MDA-MB-231, HCC 1806) and rat MTLn3 cells, CIP4 silencing had no overt effect on tumor growth, but significantly reduced the incidence of lung metastases in each tumor model. In human invasive breast cancers, high CIP4 levels was significantly associated with high tumor stage, TNBC and HER2 subtypes, and risk of progression to metastatic disease. Together, these results implicate CIP4 in promoting metastasis in TNBCs.
Insights
Cdc42-interacting protein-4 (CIP4) promotes triple-negative breast cancer (TNBC) metastasis by enhancing cell invasion. Silencing CIP4 in TNBC models reduced lung metastasis without affecting tumor growth, implicating CIP4 as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Epidermal growth factor receptor (EGFR) and Src kinase signaling pathways are crucial for triple-negative breast cancer (TNBC) cell invasion and metastasis.
- Cdc42-interacting protein-4 (CIP4) is a protein implicated in cellular processes relevant to cancer progression.
Purpose of the Study:
- To investigate the role of CIP4 in TNBC metastasis in vivo.
- To profile CIP4 expression in human breast cancer patients and correlate it with clinical parameters.
Main Methods:
- CIP4 knock-down (KD) in human TNBC cell lines (MDA-MB-231, HCC 1806) and rat MTLn3 cells.
- Assessment of Erk kinase activation and cell motility.
- 3D invasion assays using spheroid colonies.
- Mammary orthotopic xenograft assays to evaluate tumor growth and lung metastasis.
- Analysis of CIP4 expression in human invasive breast cancer tissues.
Main Results:
- CIP4 KD in TNBC cells resulted in reduced Erk kinase activation and impaired cell motility.
- CIP4 KD TNBC cells exhibited significant defects in 3D extracellular matrix invasion.
- Mammary orthotopic xenografts with CIP4-silenced cells showed no change in tumor growth but a significant reduction in lung metastases.
- High CIP4 levels in human invasive breast cancers correlated with advanced tumor stage, TNBC and HER2 subtypes, and increased risk of progression.
Conclusions:
- CIP4 plays a significant role in promoting TNBC metastasis.
- CIP4 expression levels are associated with aggressive breast cancer subtypes and metastatic potential.
- CIP4 is implicated as a key mediator of TNBC metastasis and a potential therapeutic target.
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