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DBC2, a candidate for a tumor suppressor gene involved in breast cancer
Masaaki Hamaguchi1, Jennifer L Meth, Christine von Klitzing
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. hamaguch@cshl.edu
Abstract:
A previously uncharacterized gene, DBC2 (deleted in breast cancer), was cloned from a homozygously deleted region at human chromosome 8p21. DBC2 contains a highly conserved RAS domain and two putative protein interacting domains. Our analyses indicate that DBC2 is the best candidate tumor suppressor gene from this region. It lies within the epicenter of the deletions and is homozygously deleted in 3.5% (7/200) of breast tumors. Mutation analysis of DBC2 led to discovery of two instances of somatic missense mutations in breast tumor specimens, whereas no missense mutations were found in other candidates from the region. Unlike other genes in the region, expression of DBC2 is often extinguished in breast cancer cells or tissues. Moreover, our functional analysis revealed that DBC2 expression in breast cancer cells lacking DBC2 transcripts causes growth inhibition. By contrast, expression of a somatic mutant discovered in a breast cancer specimen does not suppress the growth of breast cancer cells.
Insights
The deleted in breast cancer gene 2 (DBC2) functions as a tumor suppressor. Its deletion and loss of expression in breast cancer cells inhibit tumor growth, indicating its critical role in preventing cancer progression.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- A specific chromosomal region, 8p21, is frequently deleted in breast cancer.
- The Deleted in Breast Cancer 2 (DBC2) gene was identified within this deleted region.
Purpose of the Study:
- To investigate the role of DBC2 as a potential tumor suppressor gene in breast cancer.
- To analyze the frequency of DBC2 deletions and mutations in breast tumors.
- To evaluate the functional impact of DBC2 expression and its mutations on breast cancer cell growth.
Main Methods:
- Gene cloning and characterization of DBC2.
- Analysis of homozygous deletions and somatic mutations in breast tumor specimens.
- Quantitative assessment of DBC2 gene expression in cancer cells and tissues.
- Functional assays involving DBC2 re-expression in cancer cells.
Main Results:
- DBC2 is homozygously deleted in 3.5% of breast tumors and located at the epicenter of deletions at 8p21.
- Two somatic missense mutations in DBC2 were identified in breast tumors, with no mutations found in other candidate genes.
- DBC2 expression is frequently lost in breast cancer cells.
- Restoring DBC2 expression in deficient breast cancer cells inhibited their growth, while a somatic mutant did not.
Conclusions:
- DBC2 is a strong candidate tumor suppressor gene for breast cancer, located at chromosome 8p21.
- Loss of DBC2 expression or function through deletion or mutation contributes to breast cancer development.
- DBC2's tumor-suppressive activity is dependent on its specific sequence and expression, highlighting its therapeutic potential.
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