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Updated: Jun 3, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Aromatase inhibitors and xenograft studies
Saranya Chumsri1, Gauri J Sabnis, Timothy Howes
1Department of Medicine, University of Maryland School of Medicine and University of Maryland Greenebaum Cancer Center, Baltimore, MD 21201, USA.
Abstract:
Aromatase inhibitors (AIs) have become the front-line choice for treatment of ER+ breast cancer. Nevertheless, although patients are responsive initially, they may acquire resistance and become unresponsive to further treatment. In addition, approximately 25% of breast cancers do not express the estrogen receptor (ERα) and consequently, are innately resistant to endocrine therapy. We have investigated the mechanisms associated with this lack of treatment response using xenograft models. We found that in cells and tumors that acquired resistance to the AI letrozole therapy, expression of the ER was reduced whereas growth factor signally was enhanced, including a marked increase in HER2 expression. Treatment with trastuzumab (HER2 antibody) resulted in a significant down-regulation of HER2 and p-MAPK as well as restoration of ERα expression. Thus, when trastuzumab was added to letrozole treatment at the time of tumor progression, there was significantly prolonged tumor suppression compared to trastuzumab or letrozole alone. This suggests that inhibition of both HER2 and ERα signaling pathways are required for overcoming resistance and restoring treatment sensitivity. ER negative tumors are innately resistant to endocrine therapy. Repression of the ERα has been found to be due to epigenetic modifications such as increased methylation and histone deacetylation. We found that entinostat (ENT), a histone deacetylase inhibitor (HDACi), activated not only expression of ERα but also aromatase in MDA-MB-231 ER-negative breast cancer cells, resulting in their ability to respond to estrogen and letrozole. Treatment with ENT in combination with letrozole significantly reduced tumor growth rate in xenografts compared to control tumors (p<0.001). ENT plus letrozole treatment also prevented the colonization and growth of MDA-MB-231 cells in the lung with a significant reduction (p<0.03) in both visible and microscopic foci. These results provide a strong indication for possible use of AIs in combination with HDAC inhibitors for the treatment of ER-negative breast cancer.
Insights
Aromatase inhibitors (AIs) combined with HER2 inhibitors overcome resistance in ER+ breast cancer. Histone deacetylase inhibitors (HDACi) plus AIs treat ER-negative breast cancer by restoring estrogen receptor (ERα) expression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Aromatase inhibitors (AIs) are first-line for ER+ breast cancer but resistance develops.
- Estrogen receptor-negative (ER-) breast cancers are intrinsically resistant to endocrine therapy.
- Mechanisms of resistance and intrinsic resistance involve altered signaling pathways and epigenetic modifications.
Purpose of the Study:
- Investigate mechanisms of AI resistance in ER+ breast cancer.
- Explore therapeutic strategies to overcome resistance and treat ER- breast cancer.
- Evaluate combination therapies involving AIs, HER2 inhibitors, and HDAC inhibitors.
Main Methods:
- Xenograft models of acquired resistance to letrozole (AI) in ER+ breast cancer.
- Treatment with trastuzumab (HER2 antibody) alone and in combination with letrozole.
- Xenograft models of ER- breast cancer (MDA-MB-231 cells).
- Treatment with entinostat (HDAC inhibitor) alone and in combination with letrozole.
Main Results:
- Acquired resistance to letrozole involved reduced ER expression and enhanced HER2/growth factor signaling.
- Trastuzumab treatment restored ERα expression and, when combined with letrozole, prolonged tumor suppression.
- Entinostat activated ERα and aromatase in ER- cells, enabling response to estrogen and letrozole.
- Combination of entinostat and letrozole significantly reduced tumor growth and lung metastasis in ER- models.
Conclusions:
- Combined inhibition of HER2 and ERα signaling is crucial for overcoming acquired resistance to AIs.
- Histone deacetylase inhibitors (HDACi) in combination with AIs show promise for treating ER- breast cancer by restoring ERα expression.
- Targeting both ERα and HER2 pathways, or using epigenetic modifiers with AIs, represents a viable strategy for resistant and ER- breast cancers.
