ESTROGEN-RECEPTOR GENE ANALYSIS IN ESTROGEN RECEPTOR-POSITIVE AND RECEPTOR-NEGATIVE PRIMARY BREAST-CANCER

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 cancer s are resistant to endocrine therapy, Purpose: In this study, we exami ned the entire coding region of the ER gene in ER-positive and ER-nega tive primary breast tumors to determine whether deletions/insertions o r 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 si ngle-strand conformation polymorphism analysis, denaturing gradient ge l electrophoresis, and DNA sequencing, Results: Both ER-negative and E R-positive tumors con-neutral polymorphisms in 10 [TCT-->TCC (Ser)], 8 7 [GCG-->GCC (Ala)], 243 [CGC-->CGT (Arg)], 325 [CCC-->CCG (Pro)], and 594 [ACA-->ACG (Thr)]. There was no correlation of any of the polymor phic alleles with the ER phenotype or other clinicopathologic paramete rs including tumor type, size, grade, or stage. However, the polymorph ism in codon 325 showed a strong association with a family history of breast cancer (P = .0005), This association was observed both in preme nopausal and postmenopausal patients, Despite extensive searching in e xons 1 through 8, we found no deletions/insertions and only two missen se 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 primar y breast cancers had point mutations in the ER gene, Conclusions: In t he majority of primary breast cancers, the ER-negative phenotype is no t the result of mutations in the coding region of the ER gene, but is due to deficient ER expression at the transcriptional or post-transcri ptional level. Implications: The correlation reported previously, as w ell as our current findings, suggest that further investigations are w arranted to understand the possible linkage of the ER gene locus to he reditary breast cancer.