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A Therapeutic Target for Hormone-independent Estrogen Receptor-positive Breast Cancers

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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.

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Acknowledgments

The work was supported by funds from the Commonwealth of Massachusetts, Department of Public Health and Breast Cancer Research Grants Program and National Institutes of Health NCI Grant CA61253-07.

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Authors and Affiliations

  1. Division of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, 02115, USA

    Debajit K. Biswas, Antonio Cruz, Nicole Pettit & Arthur B. Pardee

  2. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

    George L. Mutter

Authors
  1. Debajit K. Biswas
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  2. Antonio Cruz
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  3. Nicole Pettit
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  4. George L. Mutter
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  5. Arthur B. Pardee
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Corresponding author

Correspondence to Debajit K. Biswas.

Additional information

Communicated by AB Pardee.

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Biswas, D.K., Cruz, A., Pettit, N. et al. A Therapeutic Target for Hormone-independent Estrogen Receptor-positive Breast Cancers. Mol Med 7, 59–67 (2001). https://doi.org/10.1007/BF03401839

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