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A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome
Published on: October 2, 2018
Model systems: mechanisms involved in the loss of sensitivity to letrozole
Angela Brodie1, Danijela Jelovac, Gauri Sabnis
1Department 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
Abstract:
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.
Insights
This study developed a mouse model for postmenopausal breast cancer treatment. Combining letrozole with fulvestrant effectively suppressed tumors by downregulating estrogen receptors (ER), suggesting a strategy to prevent treatment resistance.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Most breast cancer patients are postmenopausal and treated with hormone therapy.
- Estrogen receptor (ER)-positive breast cancer models are crucial for studying treatment efficacy.
- Hormone therapy resistance remains a significant clinical challenge.
Purpose of the Study:
- To develop and utilize a mouse model simulating postmenopausal ER-positive breast cancer.
- To evaluate the efficacy of combining aromatase inhibitors (letrozole) with antiestrogens (tamoxifen, fulvestrant).
- To investigate mechanisms of tumor adaptation and resistance to letrozole treatment.
Main Methods:
- MCF-7Ca human breast cancer cells transfected with aromatase were grown in immune-suppressed mice.
- Treatment strategies included letrozole, tamoxifen, and fulvestrant, both as single agents and in combination.
- Analysis of signaling protein expression (ER, MAPK cascade, Akt) in tumors during treatment.
Main Results:
- Letrozole combined with tamoxifen showed similar suppression to tamoxifen alone, less than letrozole alone.
- Tumors developed resistance to letrozole, characterized by ER upregulation followed by downregulation and activation of MAPK signaling.
- Combination of letrozole with fulvestrant resulted in 45% tumor regression and sustained suppression for 29 weeks.
Conclusions:
- Tumor adaptation to estrogen deprivation involves activating alternate signaling pathways like MAPK.
- Combining letrozole with fulvestrant, which downregulates ER, is more effective than either agent alone.
- Achieving complete estrogen blockade may prevent the development of hormone-independent signaling pathways and delay resistance.
