title: HOXB7 promotes malignant progression by activating the TGFβ signaling pathway.
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, TGFβ2 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 TGFβ2 or pharmacologic inhibition of TGFβ 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. TGFβ2 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 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 TGFβ signaling pathway.
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: Shou
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Kideok
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Hui
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: Jie
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Surgery, Transplant Surgery Division, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina.
authors.forename: Sheng
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Reisman
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, South Carolina.
authors.forename: Daping
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland. hchen@biol.sc.edu saras@jhmi.edu.
authors.forename: Saraswati
authors.initials: S
authors.lastname: Sukumar
authors.affiliation: Department of Biological Science, University of South Carolina, Columbia, South Carolina. Center for Colon Cancer Research, University of South Carolina, Columbia, South Carolina. hchen@biol.sc.edu saras@jhmi.edu.
authors.forename: Hexin
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000096:biosynthesis; D053781:Transforming Growth Factor beta2 / Q000096:biosynthesis*
chemical_list: D018398:Homeodomain Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D051900:Smad3 Protein; D053781:Transforming Growth Factor beta2; C490538:HOXB7 protein, human; C497791:Smad3 protein, mouse; C509041:TGFB2 protein, human