HOXB9 Expression Promoting Tumor Cell Proliferation and Angiogenesis Is Associated with Clinical Outcomes in Breast Cancer Patients

Seki, Hirohito; Hayashida, Tetsu; Jinno, Hiromitsu; Hirose, Shigemichi; Sakata, Michio; Takahashi, Maiko; Maheswaran, Shyamala; Mukai, Makio; Kitagawa, Yuko

doi:10.1245/s10434-012-2295-5

Cited by 43 publications

(50 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HOXB9 mRNA expression was significantly higher in poorly differentiated adenocarcinomas than in highly and moderately differentiated types of adenocarcinomas (Figure 1c) and was highly related to liver metastasis (Additional file 1: Figure S1b). Moreover, although HOXB9 did not affect the disease free survival after surgery, increased HOXB9 expression in colorectal cancer was significantly associated with a poor prognosis in overall survival (Figure 1d), as previously reported for breast cancer [14]. …”

Section: Resultssupporting

confidence: 83%

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

et al. 2014

Self Cite

View full text Add to dashboard Cite

BackgroundHomeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis.MethodsWe examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens.ResultsHOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system.ConclusionsHOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.

show abstract

Section: Resultssupporting

confidence: 83%

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our previous study, we examined 141 breast cancer tissues for HOXB9 expression by immunohistochemistry [16]. We used exactly the same cohort of tissue samples to stain for E2F1 expression.…”

Section: Resultsmentioning

confidence: 99%

“…Of 155 consecutive, invasive ductal carcinoma patients who were diagnosed as having stage I, II, or III disease and who had not received any treatment before surgery, 139 paraffin-embedded tissue specimens were available for immunohistochemical (IHC) assessment [16]. Written informed consent was taken and the study was approved by the ethics committee of the School of Medicine of Keio University.…”

Section: Methodsmentioning

confidence: 99%

“…This is likely due to its induction of TGF-β, ErbB ligands and several angiogenic factors, including VEGF, bFGF, IL-8, and ANGPTL-2; these factors contribute to increased cell motility, invasion, and angiogenesis [14], [15]. The comparison between HOXB9-positive and -negative tumors of breast cancer patients revealed a considerable difference in disease-free and overall survival rate [16]. Moreover, breast cancer cells overexpressing HOXB9 are resistant to ionizing radiation due to an enhanced DNA damage response.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An E2F1-HOXB9 Transcriptional Circuit Is Associated with Breast Cancer Progression

et al. 2014

Self Cite

View full text Add to dashboard Cite

Homeobox B9 (HOXB9), a member of the homeobox gene family, is overexpressed in breast cancer and promotes tumor progression and metastasis by stimulating epithelial-to-mesenchymal transition and angiogenesis within the tumor microenvironment. HOXB9 activates the TGFβ-ATM axis, leading to checkpoint activation and DNA repair, which engenders radioresistance in breast cancer cells. Despite detailed reports of the role of HOXB9 in breast cancer, the factors that regulate HOXB9 transcription have not been extensively examined. Here we uncover an underlying mechanism that may suggest novel targeting strategies for breast cancer treatment. To identify a transcription factor binding site (TFBS) in the HOXB9 promoter region, a dual luciferase reporter assay was conducted. Protein candidates that may directly attach to a TFBS of HOXB9 were examined by Q-PCR, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and mutation analysis. A HOXB9 promoter region from −404 to −392 was identified as TFBS, and E2F1 was a potential binding candidate in this region. The induction of HOXB9 expression by E2F1 was observed by Q-PCR in several breast cancer cell lines overexpressing E2F1. The stimulatory effect of E2F1 on HOXB9 transcription and its ability to bind the TFBS were confirmed by luciferase, EMSA and ChIP assay. Immunohistochemical analysis of 139 breast cancer tissue samples revealed a significant correlation between E2F1 and HOXB9 expression (p<0.001). Furthermore, a CDK4/6 inhibitor suppressed E2F1 expression and also reduced expression of HOXB9 and its downstream target genes. Our in vitro analysis identified the TFBS of the HOXB9 promoter region and suggested that E2F1 is a direct regulator of HOXB9 expression; these data support the strong correlation we found between E2F1 and HOXB9 in clinical breast cancer samples. These results suggest that targeting the E2F1/HOXB9 axis may be a novel strategy for the control or prevention of cancer progression and metastasis.

show abstract

“…In addition to their critical roles in development, increasing numbers of studies demonstrated that HOX family genes are associated with tumorigenicity (Chen and Sukumar, 2003; Grier et al , 2005; Shah and Sukumar, 2010) and progression including tumour growth and angiogenesis (Chen and Sukumar, 2003; Rhoads et al , 2005; Winnik et al , 2009; Sun et al , 2013). HOXB9 was known to induce tumour angiogenesis, invasion and lung metastasis in breast cancer (Hayashida et al , 2010), as well as being an important prognostic factor for clinical outcomes of breast cancer patients (Chiba et al , 2012; Morgan et al , 2012; Seki et al , 2012; Shrestha et al , 2012). HOXB9 was also found to induce epithelial-to-mesenchymal transition (EMT), a process that is associated with tumour invasion and resistance to chemotherapeutic drugs and radiations by accelerating DNA damage responses (Nguyen et al , 2009; Hayashida et al , 2010).…”

mentioning

confidence: 99%

Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients

et al. 2014

View full text Add to dashboard Cite

Background:Little is known about the tumour suppressive proteins and the underlying mechanisms that suppress colon cancer progression. Homeodomain-containing transcription factor HOXB9 plays an important role in embryogenesis and cancer development. We here aim to uncover the potential role of HOXB9 in the regulation of colon adenocarcinoma progression including epithelial-to-mesenchymal transition.Methods:HOXB9 expression in colon adenocarcinoma cells and patients was analysed by western blot and immunohistochemistry separately. Correlation between HOXB9 expressions with patients' survival was assessed by Kaplan–Meier analysis. HOXB9-regulated target gene expression was determined by RNA sequencing in HOXB9-overexpressing colon adenocarcinoma cells.Results:Elevated HOXB9 expression was identified in well-differentiated colon adenocarcinoma patients and was associated with a better overall patients' survival. Overexpression of HOXB9 inhibited colon adenocarcinoma cell growth, migration, invasion in vitro and tumour growth, liver as well as lung metastases in nude mice; whereas silencing HOXB9 promoted these functions. HOXB9 promoted colon adenocarcinoma differentiation via a mechanism that stimulates mesenchymal-to-epithelial transition, involving downregulation of EMT-promoting transcriptional factors including Snail, Twist, FOXC2 and ZEB1 and upregulation of epithelial proteins including E-cadherin, claudins-1, -4, -7, occludin and ZO-1.Conclusions:HOXB9 is a novel tumour suppressor that inhibits colon adenocarcinoma progression by inducing differentiation. Elevated expression of HOXB9 predicts a longer survival in colon adenocarcinoma patients.

show abstract

HOXB9 Expression Promoting Tumor Cell Proliferation and Angiogenesis Is Associated with Clinical Outcomes in Breast Cancer Patients

Abstract: HOXB9 expression, which promotes tumor proliferation and angiogenesis, is a significant prognostic factor in breast cancer.

Cited by 43 publications

References 32 publications

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

Bevacizumab terminates homeobox B9-induced tumor proliferation by silencing microenvironmental communication

An E2F1-HOXB9 Transcriptional Circuit Is Associated with Breast Cancer Progression

Elevated HOXB9 expression promotes differentiation and predicts a favourable outcome in colon adenocarcinoma patients

Contact Info

Product

Resources

About