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SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium
Rebecca Marlow1, Phyllis Strickland, Ji Shin Lee
1Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, California 95064, USA.
Abstract:
The genes encoding Slits and their Robo receptors are silenced in many types of cancer, including breast, suggesting a role for this signaling pathway in suppressing tumorigenesis. The molecular mechanism underlying these tumor-suppressive effects has not been delineated. Here, we show that loss of Slits, or their Robo1 receptor, in murine mammary gland or human breast carcinoma cells results in coordinate up-regulation of the Sdf1 and Cxcr4 signaling axis, specifically within mammary epithelium. This is accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma. A similar inverse correlation between Slit and Cxcr4 expression is identified in human breast tumor tissues. Furthermore, we show in a xenograft model that Slit overexpression down-regulates CXCR4 and dominantly suppresses tumor growth. These studies classify Slits as negative regulators of Sdf1 and Cxcr4 and identify a molecular signature in hyperplastic breast lesions that signifies inappropriate up-regulation of key prometastatic genes.
Insights
Slits and Robo receptors suppress breast cancer by inhibiting Sdf1/Cxcr4 signaling. Loss of Slits leads to increased Cxcr4, promoting tumor growth and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Slit and Robo signaling pathways are implicated in tumor suppression.
- The molecular mechanisms of Slit's tumor-suppressive effects, particularly in breast cancer, remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Slit signaling suppresses breast tumorigenesis.
- To investigate the relationship between Slit/Robo and the Sdf1/Cxcr4 axis in breast cancer.
Main Methods:
- Studied Slit and Robo1 expression in murine mammary gland and human breast carcinoma cells.
- Analyzed Sdf1 and Cxcr4 signaling axis expression.
- Utilized a xenograft model to assess Slit's effect on tumor growth.
Main Results:
- Loss of Slits or Robo1 up-regulates Sdf1 and Cxcr4 signaling in mammary epithelium.
- Observed hyperplastic and desmoplastic changes associated with Slit loss.
- Found an inverse correlation between Slit and Cxcr4 expression in human breast tumors.
- Slit overexpression suppressed tumor growth and down-regulated CXCR4 in a xenograft model.
Conclusions:
- Slits act as negative regulators of the Sdf1/Cxcr4 signaling axis.
- Identified a molecular signature in hyperplastic breast lesions involving prometastatic gene up-regulation.
- Slit/Robo signaling is a critical suppressor of breast tumorigenesis and metastasis.
