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HOXB 7 Promotes Malignant Progression by Activating the TGF b Signaling Pathway

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 TGFb/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFb2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFb2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFb2 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 TGFb2 or pharmacologic inhibition of TGFb signaling. Furthermore, knockdown of TGFb2 in HOXB7-overexpressing MDAMB-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. TGFb2 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 TGFb2 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 TGFb signaling pathway. Cancer Res; 75(4); 709–19. 2014 AACR.