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Updated: Jul 13, 2026
Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
Xenograft models for aromatase inhibitor studies
1Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, The Greenebaum Cancer Center, Baltimore, MD 21201, USA. abrodie@umaryland.edu
Abstract:
As several aromatase inhibitors are now available for treating breast cancer, we developed a model system to compare their antitumor efficacy and to explore strategies for their optimal use. Tumors are grown in ovariectomized, immunodeficient mice from MCF-7 human breast cancer cells transfected with the aromatase gene (MCF-7Ca) and can therefore synthesize as well as respond to estrogen. Results from this model have been predictive of clinical outcome. Thus, inhibiting estrogen action and estrogen synthesis by treating mice with the aromatase inhibitor letrozole and the antiestrogen tamoxifen in combination did not result in synergy. Moreover, when tamoxifen treatment was no longer effective, tumor growth was significantly reduced in response to sequential letrozole treatment. However, our findings indicate that letrozole alone was better than all other treatments. Although letrozole resulted in long sustained growth inhibition, tumors eventually grew despite continued treatment. Mechanisms of resistance to letrozole were investigated during the course of treatment. ER was initially upregulated in responding tumors, but subsequently decreased below control levels in tumors no longer responsive to letrozole. Her-2 as well as adapter proteins (p-Shc and Grb-2) and signaling proteins in the MAPK cascade (p-Raf, p-Mekl/2, and p-MAPK), were all increased in letrozole resistant tumors. In LTLT cells, isolated from the letrozole resistant tumors and treated with inhibitors of the MAPKinase pathway, MAPK activity was decreased and ER expression restored to control levels. Inhibitors of EGFR/Her-2 also restored the sensitivity of LTLT cells to letrozole. These results suggest that crosstalk occurs between ER and tyrosine kinase receptor signaling. Therefore, to investigate whether down-regulating ER would prevent activation of MAPK and resistance to letrozole, xenografts were treated with letrozole and faslodex in combination. Her-2 and MAPK were not increased and tumor growth was inhibited throughout 29 weeks of treatment. These results suggest that blocking both ER and growth factor mediated transcription may delay development of resistance to letrozole and maintain its growth inhibition of breast cancer.
Insights
This study explored optimal breast cancer treatment strategies using a mouse model. Combining letrozole and fulvestrant (Faslodex) effectively inhibited tumor growth and delayed resistance by blocking both estrogen receptor and growth factor signaling.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Several aromatase inhibitors are available for breast cancer treatment.
- A model system using MCF-7Ca cells in mice was developed to predict clinical outcomes.
- Estrogen receptor (ER) and tyrosine kinase receptor signaling pathways are crucial in breast cancer growth.
Purpose of the Study:
- To compare the antitumor efficacy of different aromatase inhibitors.
- To explore strategies for the optimal use of these inhibitors.
- To investigate mechanisms of resistance to letrozole and identify ways to overcome it.
Main Methods:
- Developed a xenograft model using MCF-7 human breast cancer cells transfected with the aromatase gene.
- Treated mice with letrozole (aromatase inhibitor) and tamoxifen (antiestrogen) alone and in combination.
- Investigated molecular mechanisms of letrozole resistance, including ER and MAPK pathway activation.
- Treated resistant cells and xenografts with pathway inhibitors and combination therapies (letrozole and fulvestrant).
Main Results:
- Letrozole alone was more effective than other treatments but resistance eventually developed.
- Letrozole resistance was associated with ER downregulation and increased Her-2 and MAPK signaling.
- Inhibiting MAPK or EGFR/Her-2 pathways restored letrozole sensitivity in resistant cells.
- Combination treatment with letrozole and fulvestrant prevented Her-2 and MAPK upregulation and maintained tumor growth inhibition.
Conclusions:
- Crosstalk exists between ER and tyrosine kinase receptor signaling in breast cancer.
- Blocking both ER and growth factor signaling may delay resistance to letrozole.
- Combination therapy with letrozole and fulvestrant shows promise for sustained breast cancer growth inhibition.
