Journal of Clinical Endocrinology & Metabolism, Vol 81, 1420-1427, Copyright © 1996 by Endocrine Society

ARTICLES

Novel mutations in the estrogen receptor messenger RNA in human breast cancers

LC Murphy, M Wang, A Coutt and H Dotzlaw
Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.

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.

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