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Her-2 Overexpression Increases the Metastatic Outgrowth of Breast Cancer Cells in the Brain

¹ Laboratory of Molecular Pharmacology, Women's Cancers Section, National Cancer Institute; ² Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke; and ³ Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; ⁴ Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, NIH, Frederick, Maryland; ⁵ University of Texas Health Science Center at San Antonio, San Antonio, Texas; ⁶ Brain Tumor Institute, Cleveland Clinic, Cleveland, Ohio; ⁷ University of Schleswig-Holstein Medical Center, Kiel, Germany; ⁸ Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany; and ⁹ Department of Neurosurgery, M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Diane Palmieri, Laboratory of Molecular Pharmacology, Women's Cancers Section, National Cancer Institute, NIH, Building 37, MSC 4254, Bethesda, MD 20892. Phone: 301-594-0685; Fax: 301-402-8910; E-mail: palmierd{at}mail.nih.gov.

Retrospective studies of breast cancer patients suggest that primary tumor Her-2 overexpression or trastuzumab therapy is associated with a devastating complication: the development of central nervous system (brain) metastases. Herein, we present Her-2 expression trends from resected human brain metastases and data from an experimental brain metastasis assay, both indicative of a functional contribution of Her-2 to brain metastatic colonization. Of 124 archival resected brain metastases from breast cancer patients, 36.2% overexpressed Her-2, indicating an enrichment in the frequency of tumor Her-2 overexpression at this metastatic site. Using quantitative real-time PCR of laser capture microdissected epithelial cells, Her-2 and epidermal growth factor receptor (EGFR) mRNA levels in a cohort of 12 frozen brain metastases were increased up to 5- and 9-fold, respectively, over those of Her-2–amplified primary tumors. Co-overexpression of Her-2 and EGFR was also observed in a subset of brain metastases. We then tested the hypothesis that overexpression of Her-2 increases the colonization of breast cancer cells in the brain in vivo. A subclone of MDA-MB-231 human breast carcinoma cells that selectively metastasizes to brain (231-BR) overexpressed EGFR; 231-BR cells were transfected with low (4- to 8-fold) or high (22- to 28-fold) levels of Her-2. In vivo, in a model of brain metastasis, low or high Her-2–overexpressing 231-BR clones produced comparable numbers of micrometastases in the brain as control transfectants; however, the Her-2 transfectants yielded 3-fold greater large metastases (>50 µm²; P < 0.001). Our data indicate that Her-2 overexpression increases the outgrowth of metastatic tumor cells in the brain in this model system. [Cancer Res 2007;67(9):4190–8]

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