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Hoxb7 Inhibits Transgenic HER-2/neu–Induced Mouse Mammary Tumor Onset but Promotes Progression and Lung Metastasis

¹ The Breast Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and ² Laboratory Animal Science Program, Science Applications International Corporation; and ³ HIV Drug Resistance Program, National Cancer Institute-Frederick, Frederick, Maryland

Requests for reprints: Saraswati Sukumar, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB-I Room 143, Baltimore, MD 21231-1000. Phone: 410-614-2479; Fax: 410-614-4073; E-mail: saras{at}jhmi.edu.

Key Words: neu • transgenic • Hoxb7 • mammary • tumors

Our previous studies have shown that HOXB7 mRNA is overexpressed in 50% of invasive breast carcinomas and promotes tumor progression in breast cancer cells grown as xenografts in mice. In silico analysis of published microarray data showed that high levels of HOXB7 predict a poor outcome in HER-2–positive (P = 0.046), but not in HER-2–negative breast cancers (P = 0.94). To study the function of HOXB7 in vivo in the context of HER-2 overexpression, we generated mouse mammary tumor virus (MMTV)-Hoxb7 transgenic mice, and then crossed them with MMTV-HER-2/neu transgenic mice. In the mice carrying both Hoxb7 and HER-2/neu transgenes, Hoxb7 plays a dual role in mammary tumorigenesis. In double transgenic mice, overexpression of Hoxb7 delayed tumor onset and lowered tumor multiplicity. However, consistent with the clinical data, once the tumors appeared, their growth was faster and metastasis to the lungs occurred at a higher frequency. Our data show, for the first time, that deregulated expression of Hoxb7 in mammary tumor cells can significantly modulate HER-2/neu-oncogene induced tumorigenesis in vivo. [Cancer Res 2008;68(10):3637–44]