Model systems: mechanisms involved in the loss of sensitivity to letrozole.
A number of models have been used to study the development and treatment of breast cancer. Since most breast cancer patients are postmenopausal and treated with hormone therapy, we developed a model to simulate this type of patient. Tumors of human estrogen receptor (ER)-positive breast cancer cells transfected with aromatase (MCF-7Ca) are grown in immune suppressed mice. In this model, we have explored a number of strategies to optimize the antitumor efficacy of treatment such as combining the non-steroidal aromatase inhibitor letrozole with the antiestrogens, tamoxifen. This combination resulted in tumor suppression similar to the antiestrogen alone, but was less effective than letrozole alone. Clinical findings with the non-steroidal inhibitor anastrozole in combination with tamoxifen (ATAC trial) were consistent with our results. Although letrozole was the most effective single agent tested in the model, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors adapt to growth during letrozole treatment, we determined the expression of signaling proteins in tumors during the course of letrozole treatment compared to the tumors of control mice. We found that tumors initially up regulated the ER, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the MAPK cascade (p-Raf, p-Mek1/2, and p-MAPK), but not Akt, were increased in tumors no longer responsive to letrozole. The results suggest that tumor cells adapt to estrogen deprivation during letrozole treatment by activation of alternate signaling pathways to increase transcription. When letrozole was combined with the pure antiestrogen fulvestrant, to down regulate ER, the combination was more effective than either letrozole or fulvestrant alone. Tumors regressed by 45% and were maintained without growth for the duration of the experiment (29 weeks). Down regulation of ER by fulvestrant may prevent cross talk between these signaling pathways. The results suggest that achieving more complete estrogen blockade may delay development of hormone-independent signaling pathways regulating proliferation.
Brodie
Angela
A
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Health Science Facilities 1, Room 580, 685 West Baltimore Street, Baltimore, MD 21201, USA. abrodie@umaryland.edu
Jelovac
Danijela
D
Sabnis
Gauri
G
Long
Brian
B
Macedo
Luciana
L
Goloubeva
Olga
O
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D051380:GRB2 Adaptor Protein; D006801:Humans; D000077289:Letrozole; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D009570:Nitriles; D011960:Receptors, Estrogen; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D004958:Estradiol; D000077289:Letrozole