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Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer
1Department of Pathology, Vanderbilt University, Nashville, TN 37232.
Background:
In breast cancer patients, about two thirds of the tumors are estrogen receptor (ER)-positive and one third are ER-negative. The molecular mechanisms leading to the ER-negative phenotype are poorly understood. Nearly all ER-negative and about 40% of ER-positive cancers are resistant to endocrine therapy.
Purpose:
In this study, we examined the entire coding region of the ER gene in ER-positive and ER-negative primary breast tumors to determine whether deletions/insertions or point mutations might account for the ER-negative phenotype.
Methods:
We amplified exons 1 through 8 of the ER gene in 118 ER-positive and 70 ER-negative primary breast tumors and searched for mutations by single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and DNA sequencing.
Results:
Both ER-negative and ER-positive tumors contained neutral polymorphisms in codons 10 [TCT-->TCC (Ser)], 87 [GCG-->GCC (Ala)], 243 [CGC-->CGT (Arg)], 325 [CCC-->CCG (Pro)], and 594 [ACA-->ACG (Thr)]. There was no correlation of any of the polymorphic alleles with the ER phenotype or other clinicopathologic parameters including tumor type, size, grade, or stage. However, the polymorphism in codon 325 showed a strong association with a family history of breast cancer (P = .0005). This association was observed both in premenopausal and postmenopausal patients. Despite extensive searching in exons 1 through 8, we found no deletions/insertions and only two missense mutations in codons 69 [AAC (Asn)-->AAG (Lys)] and 396 [ATG (Met)-->GTG (Val)] of the same ER-negative tumor. Thus, only 1% of the primary breast cancers had point mutations in the ER gene.
Conclusions:
In the majority of primary breast cancers, the ER-negative phenotype is not the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcriptional level.
Implications:
The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer.
Insights
The estrogen receptor (ER)-negative breast cancer phenotype is rarely caused by mutations in the ER gene. Instead, it is likely due to issues with ER gene expression, though one polymorphism is linked to hereditary breast cancer risk.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Estrogen receptor (ER)-positive breast cancer constitutes two-thirds of cases, while ER-negative tumors are less common.
- ER-negative cancers are frequently resistant to endocrine therapy, a critical treatment modality.
- The molecular underpinnings of the ER-negative phenotype remain largely unknown.
Purpose of the Study:
- To investigate the entire coding region of the ER gene in primary breast tumors.
- To determine if deletions, insertions, or point mutations in the ER gene contribute to the ER-negative phenotype.
Main Methods:
- Analysis of ER gene exons 1-8 in 118 ER-positive and 70 ER-negative breast tumors.
- Mutation detection using single-strand conformation polymorphism analysis, denaturing gradient gel electrophoresis, and DNA sequencing.
Main Results:
- No deletions or insertions were found in the ER gene.
- Only two missense mutations were identified in a single ER-negative tumor, indicating mutations account for only 1% of primary breast cancers.
- Several neutral polymorphisms were identified, with one (codon 325) showing a significant association with a family history of breast cancer.
Conclusions:
- The ER-negative phenotype in most primary breast cancers is not caused by mutations within the ER gene's coding region.
- Deficient ER expression at the transcriptional or post-transcriptional level is the likely cause of the ER-negative phenotype.
- Further research is needed to explore the potential linkage of the ER gene locus to hereditary breast cancer.