Estrogen-regulated messenger RNAs in human breast cancer cells

  • Bruce Westley
  • Felicity E. B. May
Part of the Cancer Treatment and Research book series (CTAR, volume 53)

Abstract

Estrogen-regulated RNAs have been cloned from cDNA libraries constructed from two breast cancer cell lines. Three RNAs (pNR—1, pNR—2 and pNR—25) were expressed and regulated only in estrogen-responsive cell lines, whereas the majority were expressed in all the cell lines tested but regulated only in those that were estrogen responsvie. Sequencing of the cDNA clones established that one mRNA (pNR—100) encoded cathepsin D and that another (pNR—2) corresponded to pS2 RNA. The majority of the mRNAs did not correspond to any sequence currently compiled in nucleic acid databases. Three patterns of regulation by the antiestrogen tamoxifen were identified. Tamoxifen was a full estrogen agonist for the pNR—1 RNA but a weak estrogen agonist for the pNR—2 and pNR—25 RNAs. For cathepsin D RNA, tamoxifen was an estrogen agonist, and there was synergism between estradiol and tamoxifen for the induction of the RNA over a limited range of concentrations of tamoxifen. The pNR—2 mRNA was measured in breast tumors. The pNR—2 expression was only detected in tumors expressing estrogen receptor mRNA, and pNR—2 expression was associated with response to tamoxifen in a group of patients receiving primary tamoxifen.

The estrogen responsiveness of a proportion of human breast cancers has been appreciated since the last century [1] and has provided the impetus for the development of compounds with antihormonal activity. The most widely used hormonal treatment for breast cancer is currently tamoxifen [2], which provides low toxicity palliation in approximately one third of unselected patients. The establishment of breast cancer cell lines [3] that retain estrogen receptors and whose growth is estrogen responsive has provided an amenable cell culture system for studying the mechanisms of action of estrogen and anti estrogens and for elucidating the mechanisms involved in estrogenstimulated proliferation [4].

We have been interested specifically in the control of gene expression by estrogens in breast cancer cells and, in particular, the identification of genes whose activity is regulated by estrogens and antiestrogens. The longterm aims are, first, to generate cloned probes for estrogen-regulated genes with which to analyze the molecular mechanisms of estrogen and antiestrogen action in a cell culture system. The second aim is to identify potential clinical markers of estrogen responsiveness that might be useful for predicting the response of breast cancer patients to antiestrogen therapy. Finally, any estrogen-regulated gene may potentially be involved in mediating the effects of estrogen on cell proliferation, and the cloning of such genes may increase understanding of this process.

This chapter describes the isolation of regulated mRNA sequences and their regulation by estrogens and antiestrogens. It also describes some clinical data on the expression of one estrogen-regulated RNA in breast tumors and its relationship to response to tamoxifen.

Keywords

Toxicity Phenol Agar Estrogen Cysteine 

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Copyright information

© Springer Science+Business Media New York 1991

Authors and Affiliations

  • Bruce Westley
  • Felicity E. B. May

There are no affiliations available

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