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Retinoic acid receptor antagonist BMS453 inhibits the growth of normal and malignant breast cells without activating RAR–dependent gene expression

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Abstract

To elucidate the role of RAR–dependent gene transcription in inhibiting breast cell growth, we have investigated the ability of retinoids to suppress growth of normal, immortal, and malignant breast cells. We compared the ability of alltrans retinoic acid (atRA) to activate retinoid receptors in normal, immortal, and malignant breast cells, with its ability to inhibit the growth of these cells. Our studies demonstrate that normal breast cells are more sensitive to the growth inhibitory effect of atRA than are immortal nonmalignant breast cells and breast cancer cells. atRA activated RAR–dependent gene transcription in both atRA–sensitive and –resistant breast cells as determined by transfection of a RARE–containing reporter gene. These results demonstrate that activation of RAR–dependent gene transcription by atRA is not sufficient to inhibit growth in atRA–resistant breast cancer cells. To determine whether activation of RAR–dependent gene transcription by atRA is necessary for growth inhibition, we tested the growth suppressive effect of a retinoid (BMS453) which binds RAR receptors and transrepresses AP–1 but does not activate RAR–dependent gene expression. This retinoid inhibited the growth of normal breast cells (HMEC and 184) and T47D breast cancer cells. Breast cancer cells which were resistant to atRA, were also resistant to BMS453. Normal human breast cells were most sensitive to the anti–proliferative effects of BMS453. These results indicate that in some breast cells RAR–dependent transactivation is not necessary for retinoids to inhibit growth. Instead, retinoids may suppress growth by inhibiting transcription factors such as AP–1 through transcription factor crosstalk.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, TX

    L. Yang, D. Munoz–Medellin, H-T. Kim & P.H. Brown

  2. Bristol–Myers–Squibb, Buffalo, NY

    J. Ostrowski & P. Reczek

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  1. L. Yang
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  2. D. Munoz–Medellin
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  3. H-T. Kim
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  4. J. Ostrowski
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  5. P. Reczek
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Yang, L., Munoz–Medellin, D., Kim, HT. et al. Retinoic acid receptor antagonist BMS453 inhibits the growth of normal and malignant breast cells without activating RAR–dependent gene expression. Breast Cancer Res Treat 56, 275–289 (1999). https://doi.org/10.1023/A:1006219411078

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