Effect of lapatinib on the development of estrogen receptor-negative mammary tumors in mice
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Tracy E Strecker1, Qiang Shen, Yun Zhang
1Breast Center, Department of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
Lapatinib, a selective orally available inhibitor of epidermal growth factor receptor (EGFR) and ErbB2 receptor tyrosine kinases, is a promising agent for the treatment of breast cancer. We examined the effect of lapatinib on the development of mammary tumors in MMTV-erbB2 transgenic mice, which express wild-type ErbB2 under the control of the mouse mammary tumor virus promoter and spontaneously develop estrogen receptor (ER)-negative and ErbB2-positive mammary tumors by 14 months of age. Mice were treated from age 3 months to age 15 months with vehicle (n = 17) or lapatinib (30 or 75 mg/kg body weight; n = 16 mice per group) by oral gavage twice daily (6 d/wk). All statistical tests were two-sided. By 328 days after the start of treatment, all 17 (100%) of the vehicle-treated mice vs five (31%) of the 16 mice treated with high-dose lapatinib developed mammary tumors (P < .001). Among MMTV-erbB2 mice treated for 5 months (n = 20 mice per group), those treated with lapatinib had fewer premalignant lesions and noninvasive cancers in their mammary glands than those treated with vehicle (P = .02). Lapatinib also effectively blocked epidermal growth factor-induced signaling through the EGFR and ErbB2 receptors, suppressed cyclin D1 and epiregulin mRNA expression, and stimulated p27 mRNA expression in human mammary epithelial cells and in mammary epithelial cells from mice treated for 5 months with high-dose lapatinib. Thus, cyclin D1, epiregulin, and p27 may represent useful biomarkers of lapatinib response in patients. These data suggest that lapatinib is a promising agent for the prevention of ER-negative breast cancer.
Insights
Lapatinib significantly reduced mammary tumor development in MMTV-erbB2 mice, suggesting its potential for preventing estrogen receptor-negative breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lapatinib is an oral inhibitor targeting epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases.
- MMTV-erbB2 transgenic mice spontaneously develop estrogen receptor (ER)-negative, ErbB2-positive mammary tumors.
- These mice serve as a model for studying ER-negative breast cancer development and treatment.
Purpose of the Study:
- To evaluate the efficacy of lapatinib in preventing mammary tumor development in MMTV-erbB2 transgenic mice.
- To investigate the molecular mechanisms underlying lapatinib's effects on tumor growth and signaling pathways.
Main Methods:
- MMTV-erbB2 mice were treated with vehicle or lapatinib (30 or 75 mg/kg) orally twice daily from 3 to 15 months of age.
- Tumor incidence and progression were monitored over time.
- Gene and protein expression of key signaling molecules (EGFR, ErbB2, cyclin D1, epiregulin, p27) were analyzed in mammary epithelial cells.
Main Results:
- High-dose lapatinib significantly reduced mammary tumor incidence (31% vs 100% in vehicle control, P < .001).
- Lapatinib treatment decreased premalignant lesions and noninvasive cancers after 5 months (P = .02).
- Lapatinib inhibited EGFR/ErbB2 signaling, suppressed cyclin D1 and epiregulin mRNA, and increased p27 mRNA expression.
Conclusions:
- Lapatinib demonstrates significant potential as a preventive agent for estrogen receptor-negative breast cancer.
- Cyclin D1, epiregulin, and p27 are identified as potential biomarkers for monitoring lapatinib response.
- These findings support further investigation of lapatinib for breast cancer prevention strategies.
