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Clinical & Experimental Metastasis (2005) 22: 237246 Springer 2005
DOI 10.1007/s10585-005-8115-6Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis
in a rat modelOdete Mendes, Hun-Taek Kim & George StoicaDepartment of Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station,
Texas, USAReceived 8 February 2005; accepted in revised form 30 May 2005Key words: animal model, brain metastasis, breast cancer, MMP2, MMP3, MMP9AbstractIn order to study the expression of MMP2, MMP3 and MMP9 in breast cancer brain metastasis, we used a
syngeneic rat model of distant metastasis of ENU1564, a carcinogen-induced mammary adenocarcinoma cell line.
At six weeks post inoculation we observed development of micro-metastasis in the brain. Immunohistochemistry
and Western blotting analyses showed that MMP-2, -3 and -9 proteins expressions are signicantly higher in
neoplastic brain tissue compared to normal brain tissue. These results were conrmed by RT-PCR. In situ
zymography revealed gelatinase activity within the brain metastasis. Gel zymography showed increase in MMP2
and MMP3 activity in brain metastasis. Furthermore, we were able to signicantly decrease the development of
breast cancer brain metastasis in animals by treatment with PD 166793, a selective synthetic MMP inhibitor. In
addition, PD 166793 decreased the in vitro invasive cell behavior of ENU1546. Together our results suggest that
MMP-2, -3 and -9 may be involved in the process of metastasis of breast cancer to the brain.Abbreviations: BC breast cancer; BD-IV BerlinDurkrey; IHC immunohistochemistry; MMP matrix
metalloproteinases; PBS phosphate buered saline; RT-PCR reverse transcriptase polymerase chain reaction;
TIMP tissue inhibitors of metalloproteinases; WB Western blottingIntroductionThe metastatic process of breast cancer (BC) has been
the subject of intense scrutiny. The brain is one of the
most common organs aected in the spread of BC that
ultimately results in fatal development of the disease.
Brain metastasis is an increasingly common complication in breast cancer patients [1]. Approximately 15
30% of breast cancer patients develop brain metastasis[2]. The exact role of the brain environment to the
development of the metastatic process has yet to be
claried. A suitable specic environment is important to
the development of tumor cells [3]. Many theories have
been developed to study and understand metastatic
behavior. Factors such as neoplastic cell molecular and
genetic characteristics [4] and biological environment
are thought to be determinant in the metastatic...