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Published on: June 7, 2016
Mutation analysis of the mel-18 gene that shows decreased expression in human breast cancer cell lines
Fumie Matsuo1, Ken-ichi Yano, Hiroko Saito
1Department of Molecular Diagnosis, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Background:
Mammalian mel-18 is a member of the polycomb group, and it acts as a transcriptional repressor with DNA binding activity. Murine mel-18 negatively regulates the cell cycle through the c-myc/cdc25 cascade, and mice haploinsufficient for mel-18 develop mammary gland tumors. In addition, the human homolog of mel-18 is located at 17q, on which candidate tumor suppressor genes for breast cancer have been suggested for a long time. These observations indicate that the mel-18 gene may be a tumor suppressor gene for breast cancer. To investigate this possibility, we examined the expression of mel-18 mRNA in human breast cancer cell lines and searched for mel-18 gene mutations in sporadic and familial breast cancers.
Methods:
The expression of mel-18 mRNA was examined in five breast cancer cell lines by RT-PCR, and somatic and germline mutations of the mel-18 gene were analyzed by the PCR-SSCP and sequence methods in 48 sporadic breast cancers, including 16 cases with loss of heterozygosity (LOH) at the mel-18 locus, and in 23 cases from 18 breast cancer families, respectively.
Results:
We found that most cell lines examined here showed decreased expression of mel-18 mRNA, however, no alteration other than a single nucleotide change that did not lead to amino acid alteration in one patient was identified.
Conclusion:
Our results reveal that mel-18 gene mutations are exceedingly rare in human breast cancers, and a reduction of mel-18 expression in human breast cancer cell lines would support a role for mel-18 haploinsufficiency in breast carcinogenesis.
Insights
The mel-18 gene, a potential breast cancer suppressor, showed reduced mRNA expression in most human breast cancer cell lines. However, mutations in the mel-18 gene are rare in human breast cancers, suggesting haploinsufficiency may play a role.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Mammalian mel-18 is a Polycomb group protein functioning as a transcriptional repressor.
- Mel-18 regulates the cell cycle via the c-myc/cdc25 cascade; haploinsufficiency in mice leads to mammary tumors.
- The human mel-18 homolog is located on chromosome 17q, a region implicated in breast cancer suppressor genes.
Purpose of the Study:
- To investigate the potential role of the mel-18 gene as a tumor suppressor in human breast cancer.
- To analyze mel-18 mRNA expression in human breast cancer cell lines.
- To identify mel-18 gene mutations in sporadic and familial breast cancers.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess mel-18 mRNA expression in five breast cancer cell lines.
- Polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing were employed to analyze somatic and germline mutations.
- Analysis included 48 sporadic breast cancers (16 with LOH at the mel-18 locus) and 23 cases from 18 breast cancer families.
Main Results:
- Most examined breast cancer cell lines exhibited decreased mel-18 mRNA expression.
- No significant mutations were found in sporadic or familial breast cancers, with only one non-amino acid altering nucleotide change identified.
Conclusions:
- Mutations in the mel-18 gene are exceedingly rare in human breast cancers.
- Reduced mel-18 expression in breast cancer cell lines supports a role for mel-18 haploinsufficiency in breast carcinogenesis.
- Further research is warranted to elucidate the precise mechanisms of mel-18 in breast cancer development.
