title: Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells.
abstract: 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.
authors: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Ubaldo E
authors: UE
authors: Martinez-Outschoorn
authors: Allison
authors: A
authors: Goldberg
authors: Zhao
authors: Z
authors: Lin
authors: Ying-Hui
authors: YH
authors: Ko
authors: Neal
authors: N
authors: Flomenberg
authors: Chenguang
authors: C
authors: Wang
authors: Stephanos
authors: S
authors: Pavlides
authors: Richard G
authors: RG
authors: Pestell
authors: Anthony
authors: A
authors: Howell
authors: Federica
authors: F
authors: Sotgia
authors: Michael P
authors: MP
authors: Lisanti
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D020847:Estrogen Receptor Modulators; D007004:Hypoglycemic Agents; D047908:Intracellular Signaling Peptides and Proteins; D007657:Ketone Bodies; D010087:Oxides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013629:Tamoxifen; D000077267:Fulvestrant; D019344:Lactic Acid; D004958:Estradiol; D004317:Doxorubicin; D008687:Metformin; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D000077237:Arsenic Trioxide