MBP-1 Inhibits Breast Cancer Growth and Metastasis in Immunocompetent Mice

Abstract

Breast cancer is the leading cause of cancer death among women. We have shown previously an antiproliferative effect of MBP-1 on several human cancer cells. In this study, we have examined the potential of MBP-1 as a gene therapeutic candidate in regression of breast cancer growth and metastasis in an immunocompetent mouse model. For this, we have used a mouse breast cancer cell line (EO771) and syngeneic C57BL/6 mice. EO771 cells were implanted into the mammary fat pad of C57BL/6 mice. Replication-deficient recombinant adenovirus expressing MBP-1 was administered intratumorally to determine gene therapeutic potential. The results showed a significant regression of primary and distant (lung) tumor growth. Animals exhibited prolonged survival on treatment with MBP-1 compared with the control group (dl312). Subsequent studies suggested that MBP-1 inhibits matrix metalloproteinase expression in human breast cancer cells. Cells transduced with MBP-1 displayed inhibition of migration in a wound-healing assay. The conditioned medium from MBP-1-transduced cells blocked in vitro tube formation assay and inhibited expression of several angiogenic molecules. Taken together, our study shows that MBP-1 acts as a double-edged sword by inhibiting primary and metastatic tumor growth and modulating matrix metalloproteinase expression with a therapeutic potential against breast cancer progression. [Cancer Res 2009;69(24):9354-9]

MBP-1 Upregulates miR-29b, Which Represses Mcl-1, Collagens, and Matrix Metalloproteinase-2 in Prostate Cancer Cells

“…Collagen I induces MMP-2 activation in breast cancer cells and hepatocellular carcinoma (Thompson et al, 1994; Theret et al, 2000). We demonstrated here that MMP-2 is a predicted target of miR-29b and we recently showed that MBP-1 expression reduced active MMP-2 in breast cancer cells (Kanda et al, 2009). Here we have observed that miR-29b inhibits pro-MMP-2 protein expression in PC3 cells.…”

“…Similarly, cells were transfected with miR-29b mimic or control miRNA (random sequence Pre-miR molecules, Applied Biosystems, CA) and cells lysates were prepared 48 h post-transfection. In addition, anti-miR-29b (Applied Biosystems, CA) was transfected and cell lysates prepared for immunoblot analysis at 48 h. Mcl-1 or MMP-2 expression was analyzed by Western blot using specific rabbit polyclonal antisera (Santa Cruz), followed by enhanced chemiluminescence (Amersham Biosciences, Piscataway, NJ) as described previously (Kanda et al, 2009). Relative expression level was determined by densitometry, normalized to the expression of actin (mouse monoclonal; Santa Cruz).…”

“…We have shown previously that intratumor injection of MBP-1 inhibits prostate tumor growth in xenograft nude mice, and induces cell death in a number of cancer cells without affecting the normal cell growth (Ray et al, 1995; Ghosh et al, 2002; 2005). MBP-1 was originally described to bind to and repress c-myc promoter function (Ray and Miller, 1991), but subsequent investigation has demonstrated that the tumor suppressor function of MBP-1 is not solely dependent upon c-myc repression (Ghosh et al, 2002; Kanda et al, 2009; Hsu et al, 2009). However the mechanism of MBP-1 mediated inhibition of prostate cancer cell growth is poorly understood.…”

Myc Promoter-Binding Protein-1 (MBP-1) Is a Novel Potential Prognostic Marker in Invasive Ductal Breast Carcinoma

“…Recently, it has been shown that MBP-1 overexpression results in the modulation of MMP-2 expression, the inhibition of in vitro angiogenesis and the regression of primary and metastatic breast tumor growth in an immunocompetent mouse model, [29].…”

“…Mounting evidence indicates that both α-enolase and MBP-1 might be involved in tumorigenesis of breast carcinoma [22], non-small cell lung cancer [23], [24], hepatitis C virus–related hepatocellular carcinoma [25], prostate tumor [17], [26], squamous cell carcinoma [27] and neuroblastoma [28]. It has also been shown that MBP-1 expression reduces the invasive ability of breast cancer cells both in vitro and in a mouse model [22], [29], and α-enolase may participate in the control of epithelial to mesenchymal transitions [30]. While the role of the exogenous expression of MBP-1 in transcription and cell growth regulation appears to be established, the in vivo function of this protein is poorly understood.…”