Function of Slit/Robo signaling in breast cancer

doi:10.1007/s11684-015-0416-9

Front. Med.

2015, Vol. 9

Issue (4) : 431-436 https://doi.org/10.1007/s11684-015-0416-9

REVIEW

Function of Slit/Robo signaling in breast cancer

Feng Gu,Yongjie Ma,Jiao Zhang,Fengxia Qin,Li Fu(

)

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy of the Ministry of Education; Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin 300060, China

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Abstract

Slit and Robo are considered tumor suppressors because they are frequently inactivated in various tumor tissue. These genes are closely correlated with CpG hypermethylation in their promoters. The Slit/Robo signaling pathway is reportedly involved in breast cancer development and metastasis. Overexpression of Slit/Robo induces its tumor suppressive effects possibly by inactivating the β-catenin/LEF/TCF and PI3K/Akt signaling pathways or by altering β-catenin/E-cadherin-mediated cell-cell adhesion in breast cancer cells. Furthermore, loss of Slit proteins or their Robo receptors upregulates the CXCL12/CXCR4 signaling axis in human breast carcinoma. In addition, this pathway regulates the distant migration of breast cancer cells not only by mediating the phosphorylation of the downstream molecules of CXCL12/CXCR4 and srGAPs, such as PI3K/Src, RAFTK/ Pyk2, and CDC42, but also by regulating the activities of MAP kinases. This review includes recent studies on the functions of Slit/Robo signaling in breast cancer and its molecular mechanisms.

Keywords Slit/Robo hypermethylation β-catenin CXCL12/CXCR4 migration

Corresponding Author(s): Li Fu

Online First Date: 05 November 2015 Issue Date: 26 November 2015

Cite this article:

Feng Gu,Yongjie Ma,Jiao Zhang, et al. Function of Slit/Robo signaling in breast cancer[J]. Front. Med., 2015, 9(4): 431-436.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0416-9
https://academic.hep.com.cn/fmd/EN/Y2015/V9/I4/431

Fig.1 Possible signaling pathways of the Slit/Robo complex via β-catenin in breast cancer. The LRR region in Slit, which binds to the immunoglobulin region of Robo, can initiate cell signaling cascades that regulate the proliferation, invasiveness, and migration of cells. The complex decreases Akt activity and then inhibits GSK-3β phosphorylation. Furthermore, GSK-3β dephosphorylation enhances β-catenin phosphorylation, which is recognized by the ubiquitin ligase complex that mediates β-catenin degradation. Aside from interacting with the E-cadherin/actin cytoskeletal system during the regulation of cell-cell adhesion, β-catenin also acts as a transcription factor along with the TCF/LEF family of DNA-binding proteins that regulate the expression of a subset of genes. LRR: leucine-rich repeat; AKT: protein kinase B, PKB; GSK-3β: glycogen synthase kinase 3 β; TCF/LEF: T cell factor/lymphoid enhancer factor; ub: ubiquitin; P: phosphorylated site.

Fig.2 Possible signaling pathways of the Slit/Robo complex via the CXCL12/CXCR4 axis in breast cancer. The Slit/Robo complex inhibits the migration, proliferation, motility, morphology, invasion, and growth cycle of breast cancer cells via the activity of the downstream molecules of CXCL12/CXCR4 and srGAPs, such as PI3K, FAK, RAFTK/Pyk2, p44/42 MAP kinase, Cdc42, MMP2, and MMP9. srGAPs: Slit/Robo GTPase-activating proteins; PI3K: phosphoinositide 3-kinase; FAK: focal adhesion kinase; RAFTK/Pyk2: related adhesion focal tyrosine kinase/praline-rich tyrosine kinase 2; p44/42 MAP kinase: p44/42 mitogen-activated protein kinase; PAK: p21-activated kinase; MMP: matrix metalloprotease.

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