Document Detail

Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells.
MedLine Citation:
PMID:  22041887     Owner:  NLM     Status:  MEDLINE    
Here, we show that tamoxifen resistance is induced by cancer-associated fibroblasts (CAFs). Coculture of estrogen receptor positive (ER+) MCF7 cells with fibroblasts induces tamoxifen and fulvestrant resistance with 4.4 and 2.5-fold reductions, respectively, in apoptosis compared with homotypic MCF7 cell cultures. Treatment of MCF7 cells cultured alone with high-energy mitochondrial "fuels" (L-lactate or ketone bodies) is sufficient to confer tamoxifen resistance, mimicking the effects of coculture with fibroblasts. To further demonstrate that epithelial cancer cell mitochondrial activity is the origin of tamoxifen resistance, we employed complementary pharmacological and genetic approaches. First, we studied the effects of two mitochondrial "poisons," namely metformin and arsenic trioxide (ATO), on fibroblast-induced tamoxifen resistance. We show here that treatment with metformin or ATO overcomes fibroblast-induced tamoxifen resistance in MCF7 cells. Treatment with the combination of tamoxifen plus metformin or ATO leads to increases in glucose uptake in MCF7 cells, reflecting metabolic uncoupling between epithelial cancer cells and fibroblasts. In coculture, tamoxifen induces the upregulation of TIGAR (TP53-induced glycolysis and apoptosis regulator), a p53 regulated gene that simultaneously inhibits glycolysis, autophagy and apoptosis and reduces ROS generation, thereby promoting oxidative mitochondrial metabolism. To genetically mimic the effects of coculture, we next recombinantly overexpressed TIGAR in MCF7 cells. Remarkably, TIGAR overexpression protects epithelial cancer cells from tamoxifen-induced apoptosis, providing genetic evidence that increased mitochondrial function confers tamoxifen resistance. Finally, CAFs also protect MCF7 cells against apoptosis induced by other anticancer agents, such as the topoisomerase inhibitor doxorubicin (adriamycin) and the PARP-1 inhibitor ABT-888. These results suggest that the tumor microenvironment may be a general mechanism for conferring drug resistance. In summary, we have discovered that mitochondrial activity in epithelial cancer cells drives tamoxifen resistance in breast cancer and that mitochondrial "poisons" are able to re-sensitize these cancer cells to tamoxifen. In this context, TIGAR may be a key "druggable" target for preventing drug resistance in cancer cells, as it protects cancer cells against the onset of stress-induced mitochondrial dys-function and aerobic glycolysis.
Ubaldo E Martinez-Outschoorn; Allison Goldberg; Zhao Lin; Ying-Hui Ko; Neal Flomenberg; Chenguang Wang; Stephanos Pavlides; Richard G Pestell; Anthony Howell; Federica Sotgia; Michael P Lisanti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-11-15
Journal Detail:
Title:  Cancer biology & therapy     Volume:  12     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-12-26     Completed Date:  2012-04-17     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  924-38     Citation Subset:  IM    
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
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MeSH Terms
Apoptosis / drug effects
Arsenicals / pharmacology
Breast Neoplasms / drug therapy,  metabolism*
Cell Line, Tumor
Coculture Techniques
Doxorubicin / pharmacology
Drug Resistance, Neoplasm
Estradiol / analogs & derivatives,  pharmacology,  therapeutic use
Estrogen Receptor Modulators / pharmacology*,  therapeutic use
Fibroblasts / drug effects,  metabolism
Hypoglycemic Agents / pharmacology
Intracellular Signaling Peptides and Proteins / metabolism
Ketone Bodies / metabolism
Lactic Acid / metabolism
Metformin / pharmacology
Mitochondria / drug effects*,  metabolism
Oxides / pharmacology
Poly(ADP-ribose) Polymerases / antagonists & inhibitors
Tamoxifen / pharmacology,  therapeutic use
Tumor Microenvironment* / drug effects
Grant Support
P30-CA-56036/CA/NCI NIH HHS; R01-AR-055660/AR/NIAMS NIH HHS; R01-CA-080250/CA/NCI NIH HHS; R01-CA-098779/CA/NCI NIH HHS; R01-CA-107382/CA/NCI NIH HHS; R01-CA-120876/CA/NCI NIH HHS; R01-CA-70896/CA/NCI NIH HHS; R01-CA-75503/CA/NCI NIH HHS; R01-CA-86072/CA/NCI NIH HHS
Reg. No./Substance:
0/Arsenicals; 0/C12orf5 protein, human; 0/Estrogen Receptor Modulators; 0/Hypoglycemic Agents; 0/Intracellular Signaling Peptides and Proteins; 0/Ketone Bodies; 0/Oxides; 10540-29-1/Tamoxifen; 1327-53-3/arsenic trioxide; 22X328QOC4/fulvestrant; 23214-92-8/Doxorubicin; 50-21-5/Lactic Acid; 50-28-2/Estradiol; 657-24-9/Metformin; EC Polymerases

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