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

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

Research output: Contribution to journalArticle

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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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Estrogen Receptor Modulators
Autophagy
Cell Death
Breast Neoplasms
Caspases
Caspase Inhibitors
Tamoxifen
afimoxifene
4,17 beta-dihydroxy-4-androstene-3-one
Estrogen Receptors
Cell Survival
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance. / Samaddar, Julia S.; Gaddy, Virgil Thomas; Duplantier, Jennifer; Periyasamy Thandavan, Sudharsan; Shah, Manish; Smith, Marlena J.; Browning, Darren D; Rawson, James V; Smith, Sylvia B; Barrett, John Thomas; Schoenlein, Patricia V.

In: Molecular Cancer Therapeutics, Vol. 7, No. 9, 22.10.2008, p. 2977-2987.

Research output: Contribution to journalArticle

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