A therapeutic target for hormone-independent estrogen receptor-positive breast cancers.

Abstract

BACKGROUND:

The action of the steroid hormone estradiol (E2) is mediated via interaction with a specific receptor (ER) that initiates a series of events downstream, leading to the modulation of hormone-responsive genes and cell proliferation. Antihormones also bind, but do not confer the active configuration to ER, thereby, blocking the transmission of E2-ER-initiated signals for cell proliferation. Although these compounds qualify for successful therapy of ER-positive [ER (+)] breast cancer patients, only a fraction of patients responds to antihormone treatment. In this study, the functional status of ER is determined to identify alternative targets for therapy of antihormone-resistant ER (+) breast cancers.

METHOD:

The interaction of ER with a specific DNA sequence, designated as E2 response element (ERE), was targeted to assess the functional state of ER. ER-ERE complex formation was measured by electrophoretic mobility shift assay (EMSA) and by a newly developed technique, based on the preferential binding of DNA-protein complex to a nitrocellulose membrane (NMBA) that measures both total and functional fraction of ER.

RESULTS:

The NMBA assay identified functional variants of ER among ER (+) breast cancer cell lines and breast tumor biopsy specimens. ER of (21PT) cells did not bind E2 and these cells were tamoxifen (TAM) resistant. However 21PT cells were sensitive to a calmodulin (CaM) antagonist, W7, that blocked ERE-ER complex formation.

CONCLUSIONS:

ER variants of the 21PT type were detected among breast cancer biopsy specimens, emphasizing the significance of an alternative therapeutic target for TAM-resistant ER (+) human breast cancers with compounds such as W7.

• Authors: D K Biswas, A Cruz, N Pettit, G L Mutter, A B Pardee
• Journal: Molecular medicine (Cambridge, Mass.) (Mol Med) Vol. 7 Issue 1 Pg. 59-67 (Jan 2001) ISSN: 1076-1551 [Print] England
• PMID: 11474128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calmodulin
• Enzyme Inhibitors
• Hormones
• Receptors, Estrogen
• Receptors, Progesterone
• Sulfonamides
• Tamoxifen
• Estradiol
• W 7
• Collodion

Topics

• Adult
• Aged
• Biochemistry (methods)
• Biopsy
• Breast Neoplasms (drug therapy, metabolism)
• Calmodulin (antagonists & inhibitors)
• Collodion (metabolism)
• Drug Resistance, Neoplasm
• Enzyme Inhibitors (pharmacology)
• Estradiol (metabolism)
• Female
• Hormones (pharmacology)
• Humans
• Middle Aged
• Receptors, Estrogen (analysis, metabolism)
• Receptors, Progesterone (analysis, metabolism)
• Response Elements (drug effects)
• Sulfonamides (pharmacology)
• Tamoxifen (pharmacology)
• Treatment Outcome
• Tumor Cells, Cultured