A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance

Julia S. Samaddar, Virgil T. Gaddy, Jennifer Duplantier, Sudharsan Periyasamy Thandavan, Manish Shah, Marlena J. Smith, Darren Browning, Jim Rawson, Sylvia B. Smith, John T. Barrett, Patricia V. Schoenlein

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Abstract

This study identifies macroautophagy as a key mechanism of cell survival in estrogen receptor-positive (ER+) breast cancer cells undergoing treatment with 4-hydroxytamoxifen (4-OHT). This selective ER modifier is an active metabolite of tamoxifen commonly used for the treatment of breast cancer. Our study provides the following key findings: (a) only 20% to 25% of breast cancer cells treated with 4-OHT in vitro die via caspase-dependent cell death; more typically, the antiestrogen-treated ER+ breast cancer cells express increased levels of macroautophagy and are viable; (b) 4-OHT-induced cell death, but not 4-OHT-induced macroautophagy, can be blocked by the pan-caspase inhibitor z-VAD-fmk, providing strong evidence that these two outcomes of antiestrogen treatment are not linked in an obligatory manner; (c) 4-OHT-resistant cells selected from ER+ breast cancer cells show an increased ability to undergo antiestrogen-induced macroautophagy without induction of caspase-dependent cell death; and (d) 4-OHT, when used in combination with inhibitors of autophagosome function, induces robust, caspase-dependent apoptosis of ER+, 4-OHT-resistant breast cancer cells. To our knowledge, these studies provide the first evidence that macroautophagy plays a critical role in the development of antiestrogen resistance. We propose that targeting autophagosome function will improve the efficacy of hormonal treatment of ER+ breast cancer.

Original languageEnglish (US)
Pages (from-to)2977-2987
Number of pages11
JournalMolecular cancer therapeutics
Volume7
Issue number9
DOIs
StatePublished - Oct 22 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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