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Updated: Aug 17, 2026
Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer
Mei Liu1, Amy Howes, Jacqueline Lesperance
1Program in Signal Transduction Research, The Burnham Institute, La Jolla, California 92037, USA.
Abstract:
The ErbB2 (Neu) receptor tyrosine kinase is frequently overexpressed in human breast cancers, and this phenotype correlates with a poor clinical prognosis. We examined the effects of the mammalian target of rapamycin inhibitor, rapamycin, on mammary tumorigenesis in transgenic mice bearing an activated ErbB2 (NeuYD) transgene in the absence or presence of a second transgene encoding vascular endothelial growth factor (VEGF). Treatment of NeuYD or NeuYD x VEGF mice with rapamycin dramatically inhibited tumor growth accompanied by a marked decrease in tumor vascularization. Two key events that may underlie the antitumor activity of rapamycin were decreased expression of ErbB3 and inhibition of hypoxia-inducible factor-1-dependent responses to hypoxic stress. Rapamycin exposure caused only a modest inhibition of the proliferation of tumor-derived cell lines in standard monolayer cultures, but dramatically inhibited the growth of the same cells in three-dimensional cultures, due in part to the induction of apoptotic cell death. These studies underscore the therapeutic potential of mammalian target of rapamycin inhibitors in ErbB2-positive breast cancers and indicate that, relative to monolayer cultures, three-dimensional cell cultures are more predictive in vitro models for studies of the antitumor mechanisms of rapamycin and related compounds.
Insights
The mammalian target of rapamycin inhibitor, rapamycin, significantly reduced breast tumor growth in mice by decreasing vascularization and ErbB3 expression. Three-dimensional cultures better predicted rapamycin
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- ErbB2 (Neu) receptor tyrosine kinase overexpression is common in human breast cancers, associated with poor prognosis.
- Vascular Endothelial Growth Factor (VEGF) plays a role in tumor growth and vascularization.
Purpose of the Study:
- To investigate the anti-tumor effects of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, on ErbB2-positive mammary tumorigenesis.
- To explore the mechanisms underlying rapamycin's efficacy, including its impact on tumor vascularization, ErbB3 expression, and hypoxia-inducible factor-1 (HIF-1) activity.
- To compare the predictive value of standard monolayer versus three-dimensional (3D) cell cultures for studying rapamycin's anti-cancer mechanisms.
Main Methods:
- Utilized transgenic mice with activated ErbB2 (NeuYD) and/or VEGF transgenes.
- Administered rapamycin to tumor-bearing mice and assessed tumor growth and vascularization.
- Analyzed changes in ErbB3 expression and HIF-1-dependent responses.
- Evaluated rapamycin's effect on tumor cell proliferation and apoptosis in both 2D monolayer and 3D culture models.
Main Results:
- Rapamycin treatment significantly inhibited mammary tumor growth and reduced tumor vascularization in NeuYD and NeuYD x VEGF mice.
- Key mechanisms included decreased ErbB3 expression and inhibited HIF-1-dependent responses to hypoxia.
- Rapamycin showed modest inhibition of proliferation in 2D cultures but dramatically inhibited growth and induced apoptosis in 3D cultures.
Conclusions:
- Mammalian target of rapamycin inhibitors demonstrate therapeutic potential for ErbB2-positive breast cancers.
- Rapamycin's anti-tumor activity is linked to reduced tumor vascularization, decreased ErbB3, and modulation of hypoxic responses.
- Three-dimensional cell cultures serve as more predictive in vitro models than monolayer cultures for studying rapamycin's anti-cancer mechanisms.
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