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Document Type |
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Article In Journal |
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Document Title |
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SLIT2, a Human Homologue of the Drosophila Slit2 Gene, Has Tumor Suppressor Activity and Is Frequently Inactivated in Lung and Breast Cancers SLIT2, a Human Homologue of the Drosophila Slit2 Gene, Has Tumor Suppressor Activity and Is Frequently Inactivated in Lung and Breast Cancers |
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Document Language |
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English |
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Abstract |
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Slit2 plays a vital role in axon guidance by signaling through Robo
receptors. Recent evidence suggests that Slit2 protein may function in
other settings because human and Xenopus Slit2 has been shown to inhibit
leukocyte chemotaxis. SLIT2 protein is a putative ligand for the ROBO
receptors. We recently demonstrated that ROBO1 is inactivated by promoter
region hypermethylation in <20% of human cancers; furthermore,
tumor suppressor activity has not been shown. Thus, the importance of
ROBO1 inactivation in human cancer is uncertain. Therefore, we investigated
the status of SLIT2 located at 4p15.2 in lung and breast cancers.
Although somatic SLIT2 mutations were not detected, epigenetic inactivation
was common. SLIT2 promoter methylation was detected in 59% of
breast cancer, 77% of non-small cell lung cancer, and 55% of small cell
lung cancer cell lines. In these tumor lines, SLIT2 expression was restored
by treatment with a demethylating agent. SLIT2 promoter methylation
was detected in 43% of breast cancer, 53% of non-small cell lung cancer,
and 36% of small cell lung cancer primary tumors. The majority of
methylated tumors demonstrated allelic loss at 4p15.2. In addition, SLIT2
expression was down-regulated in methylated breast tumors, relative to
normal control, as demonstrated by quantitative real-time reverse transcription-
PCR. Overexpression of SLIT2 suppressed >70% of colony
growth in each of three breast tumor lines (with either absent or low
SLIT2 expression). Because SLIT2 is primarily a secreted protein, SLIT2-
conditioned medium suppressed the growth of several breast cancer lines
(with absent or weak SLIT2 expression) by 26–51% but had no significant
effect on a breast tumor cell line that expresses normal levels of SLIT2.
These findings demonstrate that SLIT2 is frequently inactivated in lung
and breast cancer by promoter region hypermethylation and allele loss
and is an excellent candidate for the lung and breast tumor suppressor
gene previously mapped to 4p15.2. |
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ISSN |
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1538-7445 |
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Journal Name |
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CANCER RESEARCH |
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Volume |
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62 |
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Issue Number |
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20 |
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Publishing Year |
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1423 AH
2002 AD |
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Article Type |
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Article |
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Added Date |
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Monday, April 26, 2010 |
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Researchers
| أشرف دلول | Dallol, Ashraf | Researcher | Doctorate | |
| فريدة لطيف | latif, Farida | Investigator | Doctorate | flatif@hgmp.mrc.ac.uk |
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