Novel mutations in the estrogen receptor messenger RNA in human breast cancers.
One mechanism that has been suggested to play a role in the progression of human breast cancer from hormone dependence to independence is the expression or altered expression of mutant and/or variant forms of estrogen receptor (ER). Two major types of variant ER messenger (m)RNA have been identified in human breast biopsy samples so far: truncated transcripts and exon deleted transcripts. In this study we provide data indicating the existence of a novel type of abnormal ER mRNA. These transcripts were identified as larger than wild-type ER mRNA RT-PCR products in 9.4% of 212 human breast tumors analyzed. The data suggest nucleotide insertions are present in ER mRNA of some breast tumors. Cloning and sequencing of the larger RT-PCR products showed three different types: a complete duplication of exon 6 occurring in 7.5% of tumors; a complete duplication of both exons 3 and 4 occurring in 1 tumor; and a 69 nucleotide insertion between exons 5 and 6 occurring in 3 tumors. Open reading frame analysis suggested that exon 6 duplicated transcripts encoded a 51.4 kDa ER-like protein truncated just after exon 6 sequences; the exon 3 and 4 duplicated transcript encoded a 83.3 kDa protein containing duplication of ER amino acid residues encoded by exons 3 and 4; the 69 nucleotide insertion was inframe, adding 23 novel amino acid residues between residues 412 and 413 of the normal ER protein to produce a 68.8 kDa protein. It is unknown if these novel ER-like mRNAs are stably translated in vivo. Any resulting protein would be structurally altered, however, possibly resulting in altered function.
Murphy
L C
LC
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Wang
M
M
Coutt
A
A
Dotzlaw
H
H
D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D017931:DNA Primers; D004251:DNA Transposable Elements; D005091:Exons; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis* / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid; D014158:Transcription, Genetic
D017931:DNA Primers; D004251:DNA Transposable Elements; D012333:RNA, Messenger; D011960:Receptors, Estrogen