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Updated: Aug 8, 2026
Generating a Murine Orthotopic Metastatic Breast Cancer Model and Performing Murine Radical Mastectomy
Published on: November 29, 2018
Mammary glands reconstituted with Neu/ErbB2 transformed HC11 cells provide a novel orthotopic tumor model for testing
R Brandt1, A M Wong, N E Hynes
1Novartis Pharma AG, Oncology/Dept. of in vivo Pharmacology, WLK 125.142, CH-4002 Basel, Switzerland.
Abstract:
The ErbB2 receptor tyrosine kinase (RTK) has been intensely pursued as a cancer therapy target due to its association with breast cancer. In this study we used the HC11 mammary epithelial cell line to develop an orthotopic, ErbB2-driven tumor model for testing efficacy of anti-cancer compounds. HC11 cells were infected with a retrovirus encoding oncogenic NeuT, the rat homolog of ErbB2. Drug-selected populations were introduced into mammary fat pads of Balb/c syngeneic mice cleared of host tissue. The majority of glands injected with HC11-NeuT cells developed mammary tumors which appeared after a 3-4 week latency period and grew rapidly. HC11 cells infected with the control retrovirus showed no tumor growth after injection. Tumor-bearing mice were used to compare the in vivo efficacy of two anti-cancer agents: PKI166, a kinase inhibitor selective for EGF receptor and ErbB2, and Taxol, a microtubule assembly blocker. PKI166 inhibited NeuT-induced mammary tumor growth in a dose-dependent manner and at a dose below the maximum tolerated dose (MTD) was significantly more inhibitory than Taxol at its MTD (57% vs. 25% tumor regression). Importantly, there was a dose-dependent decrease in the phosphotyrosine content of NeuT isolated from PKI166-treated, tumor-bearing mice, providing a mechanistic link between kinase inhibition and its anti-tumor activity. Thus, implantation of genetically manipulated HC11 cells into mammary glands appears to be an excellent model for studying effects of anti-cancer agents in an orthotopic site.
Insights
A novel orthotopic breast cancer model using genetically modified HC11 cells was developed. This model effectively tested anti-cancer agents, with PKI166 showing superior efficacy in inhibiting ErbB2-driven tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The ErbB2 receptor tyrosine kinase (RTK) is a significant target in breast cancer therapy.
- Developing effective orthotopic models is crucial for evaluating anti-cancer drug efficacy.
Purpose of the Study:
- To establish an orthotopic, ErbB2-driven mammary tumor model in mice for anti-cancer compound testing.
- To compare the in vivo efficacy of PKI166 and Taxol in this novel model.
Main Methods:
- Genetically engineered HC11 mammary epithelial cells with oncogenic NeuT (ErbB2 homolog).
- Implanted modified HC11 cells into the mammary fat pads of Balb/c mice.
- Administered anti-cancer agents PKI166 and Taxol to tumor-bearing mice and assessed tumor growth and phosphotyrosine content.
Main Results:
- HC11-NeuT cells formed orthotopic mammary tumors with a 3-4 week latency.
- PKI166 demonstrated dose-dependent inhibition of tumor growth, significantly outperforming Taxol.
- PKI166 treatment led to a dose-dependent decrease in NeuT phosphotyrosine levels, confirming kinase inhibition.
Conclusions:
- The developed orthotopic mammary tumor model is a valuable tool for evaluating anti-cancer agents targeting ErbB2.
- PKI166 exhibits potent anti-tumor activity in an ErbB2-driven cancer model, superior to Taxol.
- The model provides mechanistic insights into drug action by correlating kinase inhibition with tumor regression.
