The purpose of this study was to investigate the expression of Y-Box-binding protein 1 (YB-1) in breast cancer and its correlation with clinicopathological characteristics and prognosis. Paraffin sections were retrospectively collected from 239 cases of stage I-III breast cancer patients and 30 healthy females who received surgery between January 2000 and December 2004 in the Chinese People's Liberation Army General Hospital. The protein expression of YB-1 was detected by immunohistochemistry. The expression difference between the two groups and the correlation between YB-1 expression and clinicopathological characteristics and breast cancer prognosis were analyzed. Within the breast cancer group, YB-1 was expressed in the cytoplasm in 100.0% (239/239) of cases and in the nucleus in 36.8% (88/239) of cases. Within the control group of normal breast tissue, YB-1 was expressed in the cytoplasm in 100.0% (30/30) of cases and in the nucleus in 16.7% (5/30) of cases. The expression of YB-1 in the nucleus of breast cancer cells was significantly higher than that in normal breast tissue (P = 0.029). The expression of YB-1 in the nucleus of breast cancer cells positively correlated with the Scarff-Bloom-Richardson grade (P = 0.007) and HER-2 expression (P = 0.005), negatively correlated with ER expression (P = 0.004), and was independent of the age, menstrual status, pathological type, tumor size, lymph node status, presence of thrombosis, PR expression, and EGFR expression. The 5-year disease-free survival (DFS) and overall survival (OS) of patients with positive YB-1 expression in the nucleus were significantly lower than those of patients who were negative for nuclear YB-1 expression, and the difference was statistically significant (DFS 65.9% vs. 82.1%, P = 0.000; OS 79.5% vs. 92.1%, P = 0.000). Multivariate analysis suggested that the expression of YB-1 in the nucleus is an independent prognostic factor that affects DFS and OS in breast cancer patients (DFS P = 0.015; OS P = 0.035). In conclusion, the expression of YB-1 in the nucleus is related to carcinogenesis and the development of breast cancer. Therefore, YB-1 is an important molecular marker that can be used to predict breast cancer prognosis.
Background: The combination of large-scale screening platforms and animal models of cancer, have provided much insight into the genetic mechanisms that control metastatic progression. Indeed, several studies have unraveled an essential role for genes that encode growth factors and extracellular matrix proteins in the progression of breast cancer. We have found that one such growth factor, bone morphogenic protein-4 (BMP4), to be significantly reduced in tumors with a high proclivity to metastasize. BMP4 is known to regulate tissue polarity and differentiation during embryogenesis, however it is not known whether BMP4 can functionally affect tumor progression. Methods and results: In a panel of mammary tumor lines, we demonstrate an inverse correlation between metastatic propensity and the expression of BMP4 through a combination of RT-PCR, immunohistochemistry (IHC) and ELISA. These findings were extended to publicly available gene expression data sets, where low BMP4 expression was found to be associated with ER-negative breast tumors and in those tumors with high histologic grade. Low BMP4 expression also correlated with poorer survival from distant metastases (HR 0.82, p = 0.013). IHC analysis on a tissue microarray consisting of tumor specimens from 535 patients with invasive breast cancer demonstrated that, compared to normal breast epithelium, BMP4 positivity was significantly less common in both DCIS (HR 0.59, p = 0.00046) and invasive carcinoma (HR = 0.56, p<0.0000001), and was inversely associated with axillary lymph node-positivity (HR = 1.53, p = 0.055). Using surrogate in vitro assays of metastasis, we determined that BMP4 can suppress the ability of highly metastatic 4T1.2 tumor cells to resist anoikis. When BMP4 was overexpressed in 4T1.2 cells (4T1.2-BMP4) and orthotopically implanted in mice, we did not observe an effect on primary tumor growth, however elevated BMP4 expression did block the ability of these tumors to metastasize to the lymph node, lung and bone. In a reverse-complimentary approach, we confirmed that silencing of BMP4 expression by RNAi in weakly metastatic 4T07 and 168FARN cells, can enhance lung colonization. Mechanistically, we establish that BMP4 can induce canonical BMP-SMAD signaling in multiple breast cancer cells, leading to an up-regulation of genes known to suppress metastasis, and a down-regulation of metastasis promoting genes. Specifically, we link the anti-metastatic function of BMP4 to its ability to induce the expression of the known metastasis suppressor, Smad7. Through RNAi-mediated suppression of Smad7 in 4T1.2-BMP4 tumors, we were able to restore the metastatic phenotype of this tumor line. Finally, we demonstrate that administration of recombinant BMP4 protein in 4T1.2 tumor challenged mice elevates Smad7 expression within the primary tumor, and leads to a pronounced decrease in spontaneous bone and lung metastasis. Conclusion: Utilizing animal models of cancer, and clinically sourced tissues, we provide correlative and functional data to prove that BMP4 is a bona fide metastasis suppressor gene in breast cancer. Furthermore, we demonstrate that BMP4 may be therapeutically viable, and can prevent breast tumor progression through the modulation of known ‘metastasis virulence’ genes. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-03.
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