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Progressive loss of Syk and abnormal proliferation in breast cancer cells
Maria Moroni1, Viatcheslav Soldatenkov, Li Zhang
1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, USA.
Abstract:
The tumor suppressor gene Syk tyrosine kinase is absent or reduced in invasive breast cancer tissues and cell lines; its loss in breast tissues is linked to poor prognosis and metastasis. Also, evidence shows that in vitro Syk is involved in regulating proliferation. Here, we show by in situ hybridization on breast tissue sections that the loss of Syk expression is progressive during tumor development. Strikingly, Syk is already partially lost in normal epithelial tissue adjacent to the cancer lesion. In vivo, cell proliferation (as measured by the proliferative index Ki67) increased from normal to ductal carcinoma in situ to invasive, whereas Syk in situ staining in the same tissues decreased. In vitro, the presence of Syk was associated with reduced cell proliferation in an epidermal growth factor receptor-overexpressing breast cancer cell line, BT549, whereas changes in apoptosis were undetected. Concomitantly, the kinase activity of the proto-oncogene Src was reduced by approximately 30%. A 5-fold increase in abnormal mitoses was observed in the Syk-transfected cells compared with vector control. We propose that Syk is involved in the regulation of cell proliferation, possibly by controlling mechanisms of mitosis and cytokinesis via Src signal transduction pathway(s). Because of its progressive and early loss during tumor onset and development, monitoring of Syk loss in breast epithelial cells by noninvasive techniques such as ductal lavage may be a powerful tool for screening purposes.
Insights
The tumor suppressor Syk tyrosine kinase is progressively lost in breast cancer, correlating with increased cell proliferation. Monitoring Syk loss may aid early breast cancer detection.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Syk tyrosine kinase is a tumor suppressor gene often reduced in invasive breast cancer.
- Loss of Syk expression is linked to poor prognosis and metastasis in breast cancer.
- Previous studies suggest Syk regulates cell proliferation in vitro.
Purpose of the Study:
- To investigate the role of Syk tyrosine kinase in breast tumor development and progression.
- To determine the relationship between Syk expression levels and cell proliferation.
- To explore the potential of Syk loss as an early screening marker for breast cancer.
Main Methods:
- In situ hybridization on breast tissue sections to assess Syk expression.
- Analysis of Ki67 proliferative index in normal, in situ, and invasive breast tissues.
- In vitro studies using a Syk-deficient breast cancer cell line (BT549) and Syk transfection.
- Measurement of Src kinase activity and assessment of mitotic abnormalities.
Main Results:
- Syk expression progressively decreases during breast tumor development, starting in adjacent normal tissue.
- Increased cell proliferation (Ki67) inversely correlates with Syk expression from normal to invasive stages.
- Syk presence in BT549 cells reduced proliferation and Src kinase activity, and decreased abnormal mitoses.
- Apoptosis remained unchanged in Syk-manipulated cells.
Conclusions:
- Syk tyrosine kinase plays a role in regulating breast cell proliferation, potentially through mitosis and cytokinesis, involving the Src signaling pathway.
- Progressive and early loss of Syk during tumorigenesis suggests its utility as an early detection biomarker.
- Noninvasive monitoring of Syk loss, such as via ductal lavage, could be a valuable breast cancer screening tool.
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