A role for macroautophagy in protection against 4-hydroxytamoxifen-induced cell death and the development of antiestrogen resistance.
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.
Samaddar
Julia S
JS
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.
Gaddy
Virgil T
VT
Duplantier
Jennifer
J
Thandavan
Sudharsan Periyasamy
SP
Shah
Manish
M
Smith
Marlena J
MJ
Browning
Darren
D
Rawson
Jim
J
Smith
Sylvia B
SB
Barrett
John T
JT
Schoenlein
Patricia V
PV
D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D053453:Caspase 9 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005260:Female; D006801:Humans; D010588:Phagosomes / Q000187:drug effects / Q000648:ultrastructure; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology
D020847:Estrogen Receptor Modulators; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D053453:Caspase 9