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Publication : HOXB7 promotes malignant progression by activating the TGFβ signaling pathway.

First Author  Liu S Year  2015
Journal  Cancer Res Volume  75
Issue  4 Pages  709-19
PubMed ID  25542862 Mgi Jnum  J:218826
Mgi Id  MGI:5618559 Doi  10.1158/0008-5472.CAN-14-3100
Citation  Liu S, et al. (2015) HOXB7 Promotes Malignant Progression by Activating the TGFbeta Signaling Pathway. Cancer Res 75(4):709-19
abstractText  Overexpression of HOXB7 in breast cancer cells induces an epithelial-mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double-transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFbeta/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFbeta2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFbeta2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFbeta2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFbeta2 or pharmacologic inhibition of TGFbeta signaling. Furthermore, knockdown of TGFbeta2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFbeta2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFbeta2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non-cell-autonomous manner through activation of the TGFbeta signaling pathway. Cancer Res; 75(4); 709-19. (c)2014 AACR.
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