Slit-2 induces a tumor-suppressive effect by regulating beta-catenin in breast cancer cells.
SLIT-2 is considered as a candidate tumor suppressor gene, because it is frequently inactivated in various cancers due to hypermethylation of its promoter region and allelic loss. However, the exact mechanism of its tumor-suppressive effect has not been elucidated. Here, we observed that Slit-2-overexpressing breast cancer cells exhibited decreased proliferation and migration capabilities compared with control cells under in vitro conditions. These results were confirmed in vivo in mouse model systems. Mice injected with MCF-7/Slit-2 cells showed a 60-70% reduction in tumor size compared with mice injected with MCF-7/VC cells both in the absence and presence of estrogen. Upon further elucidation, we observed that Slit-2 mediates the tumor-suppressive effect via a coordinated regulation of the beta-catenin and PI3K signaling pathways and by enhancing beta-catenin/E-cadherin-mediated cell-cell adhesion. Our study for the first time reveals that Slit-2-overexpressing breast cancer cells exhibit tumor suppressor capabilities through the novel mechanism of beta-catenin modulation.
Prasad
Anil
A
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. abailugu@bidmc.harvard.edu
Paruchuri
Vikram
V
Preet
Anju
A
Latif
Farida
F
Ganju
Ramesh K
RK
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000096:biosynthesis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D019656:Loss of Heterozygosity; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D051176:beta Catenin / Q000096:biosynthesis*; D000098552:Slit Homolog 2 Protein
D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D000098552:Slit Homolog 2 Protein