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Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER+ breast cancer cells

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Abstract

Postmenopausal women with estrogen receptor positive (ER+) breast cancer frequently respond paradoxically to estrogen administration with tumor regression. Using both LTED and E8CASS cells derived from MCF-7 breast cancer cells by long-term estrogen-deprivation, we previously reported that 17β -estradiol (estradiol) is a powerful, pro-apoptotic hormone which kills the cancer cells through activation of the Fas/FasL death receptor pathway. We postulated that the mitochondrial interactive protein Bcl-2 might play a role in the regulation of estradiol-induced apoptosis in both LTED and E8CASS cells. In this study, we assessed estradiol effects on cell growth, proliferation and apoptosis. Additionally we investigated the effect of estradiol on caspase activation, NF-KB and Bcl-2 expression. The functional role of Bcl-2 in estradiol-induced apoptosis was further studied by knockdown or decrease of Bcl-2 with siRNA. Our results show that estradiol significantly inhibited cell growth primarily through a pro-apoptotic action involving caspase-7 and 9 activations (p < 0.01). Basal Bcl-2 and NF-KB levels were greatly elevated and estradiol decreased NF-KB, but not Bcl-2 expression. Knockdown of Bcl-2 expression with siRNA decreased the levels of this protein by 9 fold (p < 0.01). This reduction markedly sensitized both LTED and E8CASS cells to the pro-apoptotic action of estradiol, leading to a synergistic induction of apoptosis and a concomitant reduction in cell number (p < 0.01). Therefore, down-regulation of Bcl-2 synergistically enhanced estradiol-induced apoptosis in ER+ postmenopausal breast cancer cells.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA

    R. X.-D Song, Z. Zhang, G. Mor & R. J. Santen

  2. Division of Endocrinology, University of Virginia Health Science Center, Charlottesville, VA, 22903, USA

    R. X.-D Song

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  1. R. X.-D Song
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  2. Z. Zhang
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  3. G. Mor
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  4. R. J. Santen
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Correspondence to R. X.-D Song.

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Song, R.XD., Zhang, Z., Mor, G. et al. Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER+ breast cancer cells. Apoptosis 10, 667–678 (2005). https://doi.org/10.1007/s10495-005-1903-2

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  • DOI: https://doi.org/10.1007/s10495-005-1903-2

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