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Journal of the National Cancer Institute Advance Access originally published online on January 13, 2009
JNCI Journal of the National Cancer Institute 2009 101(2):107-113; doi:10.1093/jnci/djn436
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© The Author 2009. Published by Oxford University Press.

Effect of Lapatinib on the Development of Estrogen Receptor–Negative Mammary Tumors in Mice

Tracy E. Strecker, Qiang Shen, Yun Zhang, Jamal L. Hill, Yuxin Li, Chunyu Wang, Hee-Tae Kim, Tona M. Gilmer, Krystal R. Sexton, Susan G. Hilsenbeck, C. Kent Osborne, Powel H. Brown

Affiliations of authors: Breast Center, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX (TES, QS, YZ, JLH, YL, CW, H-TK, KRS, SGH, CKO, PHB); Department of Oncology Translational Research, GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC (TMG)

Correspondence to: Powel H. Brown, MD, PhD, Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM600, Houston, TX 77030 (e-mail: pbrown{at}bcm.edu).

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.


CONTEXT AND CAVEATS

Prior knowledge

A small-molecule tyrosine kinase inhibitor specific for epidermal growth factor receptor (EGFR)—gefitinib—only partially prevents the development of estrogen receptor (ER)–negative mammary tumors in MMTV-erbB2 transgenic mice, which spontaneously develop ER-negative and ErbB2-positive mammary tumors by 14 months of age.

Study design

An examination of the effect of lapatinib, a dual kinase inhibitor that blocks the kinase activities of both EGFR and ErbB2, on mammary tumorigenesis in MMTV-erbB2 transgenic mice.

Contribution

Compared with vehicle-treated mice, lapatinib suppressed the development of ER-negative and ErbB2-positive invasive mammary tumors in MMTV-erbB2 mice treated for 12 months and the numbers of premalignant lesions and noninvasive cancers in the mammary glands of mice treated for 5 months.

Implications

Lapatinib may be useful for the prevention of ER-negative, ErbB2-positive breast cancer in humans.

Limitations

The effect of lapatinib was studied in only one mouse model. Lapatinib did not completely prevent mammary tumorigenesis in the MMTV-erbB2 mice.

From the Editors

 
Manuscript received November 21, 2007; revised October 17, 2008; accepted October 28, 2008.


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