HOXB7 promotes malignant progression by activating the TGFβ signaling pathway

Shou Liu, Kideok Jin, Yvonne Hui, Jie Fu, Chunfa Jie, Sheng Feng, David Reisman, Qian Wang, Daping Fan, Saraswati Sukumar, Hexin Chen

Research output: Contribution to journalArticle

Abstract

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 TGFβ/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 TGFβ2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFβ2 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 TGF β2 or pharmacologic inhibition of TGF β signaling. Furthermore, knockdown of TGFβ2 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. TGF β2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these fi ndings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFβ2 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 TGF β signaling pathway.

Original languageEnglish (US)
Pages (from-to)709-719
Number of pages11
JournalCancer Research
Volume75
Issue number4
DOIs
StatePublished - Feb 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Liu, S., Jin, K., Hui, Y., Fu, J., Jie, C., Feng, S., Reisman, D., Wang, Q., Fan, D., Sukumar, S., & Chen, H. (2015). HOXB7 promotes malignant progression by activating the TGFβ signaling pathway. Cancer Research, 75(4), 709-719. https://doi.org/10.1158/0008-5472.CAN-14-3100