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Published in: Annals of Surgical Oncology 6/2012

01-06-2012 | Breast Oncology

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

Authors: Hirohito Seki, MD, Tetsu Hayashida, MD, PhD, Hiromitsu Jinno, MD, PhD, Shigemichi Hirose, MD, PhD, Michio Sakata, MD, Maiko Takahashi, MD, Shyamala Maheswaran, PhD, Makio Mukai, MD, PhD, Yuko Kitagawa, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Issue 6/2012

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Abstract

Background

Studies have suggested that HOXB9 expression in breast cancer cells promotes cellular invasiveness, metastatic ability, and tumor neovascularization in the surrounding tissue in in vitro and in vivo assays. These findings imply that HOXB9 overexpression may alter tumor-specific cell fates and the tumor stromal microenvironment, contributing to breast cancer progression. The objective of this study was to analyze whether these results could be applied to clinical practice.

Methods

A total of 141 consecutive, invasive ductal carcinoma patients who underwent surgical treatment were examined. Immunohistochemical staining was performed to evaluate the expression of HOXB9, Ki-67, CD31, and CD34, and the association of tumor proliferation and angiogenesis with HOXB9 expression was analyzed.

Results

Of the 141 tumor specimens immunostained for HOXB9, 69 (48.9%) stained positive. Larger primary tumor size, hormone receptor negativity, HER2 positivity, higher nuclear grade, and number of pathologic nodal metastases were significant variables associated with HOXB9 expression. Notably, 12 (92.3%) of 13 triple-negative breast cancer cases showed HOXB9 expression. Disease-free survival and overall survival were significantly different between the HOXB9-positive and HOXB9-negative groups (hazard ratio 20.714, P = 0.001; and hazard ratio 9.206, P = 0.003, respectively). Multivariate analysis indicated that HOXB9 expression was the only independent prognostic factor for disease-free survival (hazard ratio 15.532, P = 0.009). HOXB9-positive tumors showed a significant increase in the number of vasculature and the Ki-67 ratio compared with HOXB9-negative tumors.

Conclusions

HOXB9 expression, which promotes tumor proliferation and angiogenesis, is a significant prognostic factor in breast cancer.
Appendix
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Literature
1.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRef
2.
go back to reference Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20:1319–29.PubMedCrossRef Goldhirsch A, Ingle JN, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol. 2009;20:1319–29.PubMedCrossRef
3.
go back to reference Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2002;2:777–85.PubMedCrossRef Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2002;2:777–85.PubMedCrossRef
4.
go back to reference Hatzis P, van der Flier LG, van Driel MA, et al. Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Mol Cell Biol. 2008;28:2732–44.PubMedCrossRef Hatzis P, van der Flier LG, van Driel MA, et al. Genome-wide pattern of TCF7L2/TCF4 chromatin occupancy in colorectal cancer cells. Mol Cell Biol. 2008;28:2732–44.PubMedCrossRef
5.
go back to reference Calvo R, West J, Franklin W, et al. Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci USA. 2000;97:12776–81.PubMedCrossRef Calvo R, West J, Franklin W, et al. Altered HOX and WNT7A expression in human lung cancer. Proc Natl Acad Sci USA. 2000;97:12776–81.PubMedCrossRef
6.
go back to reference Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138:51–62.PubMedCrossRef Nguyen DX, Chiang AC, Zhang XH, et al. WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009;138:51–62.PubMedCrossRef
7.
go back to reference Hayashida T, Takahashi F, Chiba N, et al. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci USA. 2010;107:1100–5.PubMedCrossRef Hayashida T, Takahashi F, Chiba N, et al. HOXB9, a gene overexpressed in breast cancer, promotes tumorigenicity and lung metastasis. Proc Natl Acad Sci USA. 2010;107:1100–5.PubMedCrossRef
8.
go back to reference Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.PubMedCrossRef Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.PubMedCrossRef
9.
go back to reference Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl. 16):15–8.PubMed Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002;29(6 Suppl. 16):15–8.PubMed
10.
go back to reference Linderholm BK, Hellborg H, Johansson U, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20:1639–46.PubMedCrossRef Linderholm BK, Hellborg H, Johansson U, et al. Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer. Ann Oncol. 2009;20:1639–46.PubMedCrossRef
11.
go back to reference Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.PubMed Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155–68.PubMed
12.
go back to reference Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474–81.PubMed Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17:1474–81.PubMed
13.
go back to reference Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.PubMedCrossRef Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10:5367–74.PubMedCrossRef
14.
go back to reference al-Sader MH, Doyle E, Kay EW, et al. Proliferation indexes—a comparison between cutaneous basal and squamous cell carcinomas. J Clin Pathol. 1996;49:549–51.PubMedCrossRef al-Sader MH, Doyle E, Kay EW, et al. Proliferation indexes—a comparison between cutaneous basal and squamous cell carcinomas. J Clin Pathol. 1996;49:549–51.PubMedCrossRef
15.
go back to reference Cattoretti G, Becker MH, Key G, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.PubMedCrossRef Cattoretti G, Becker MH, Key G, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.PubMedCrossRef
16.
go back to reference McCormick D, Chong H, Hobbs C, Datta C, Hall PA. Detection of the Ki-67 antigen in fixed and wax-embedded sections with the monoclonal antibody MIB1. Histopathology. 1993;22:355–60.PubMedCrossRef McCormick D, Chong H, Hobbs C, Datta C, Hall PA. Detection of the Ki-67 antigen in fixed and wax-embedded sections with the monoclonal antibody MIB1. Histopathology. 1993;22:355–60.PubMedCrossRef
17.
go back to reference McCormick D, Yu C, Hobbs C, Hall PA. The relevance of antibody concentration to the immunohistological quantification of cell proliferation–associated antigens. Histopathology. 1993;22:543–7.PubMedCrossRef McCormick D, Yu C, Hobbs C, Hall PA. The relevance of antibody concentration to the immunohistological quantification of cell proliferation–associated antigens. Histopathology. 1993;22:543–7.PubMedCrossRef
18.
go back to reference Bluff JE, Menakuru SR, Cross SS, et al. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br J Cancer. 2009;101:666–72.PubMedCrossRef Bluff JE, Menakuru SR, Cross SS, et al. Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease. Br J Cancer. 2009;101:666–72.PubMedCrossRef
19.
go back to reference Davies G, Salter J, Hills M, Martin LA, Sacks N, Dowsett M. Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clin Cancer Res. 2003;9:2651–6.PubMed Davies G, Salter J, Hills M, Martin LA, Sacks N, Dowsett M. Correlation between cyclooxygenase-2 expression and angiogenesis in human breast cancer. Clin Cancer Res. 2003;9:2651–6.PubMed
20.
go back to reference Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol. 2009;183:3170–6.PubMedCrossRef Goodman WA, Levine AD, Massari JV, Sugiyama H, McCormick TS, Cooper KD. IL-6 signaling in psoriasis prevents immune suppression by regulatory T cells. J Immunol. 2009;183:3170–6.PubMedCrossRef
21.
go back to reference Zhou D, Cheng SQ, Ji HF, et al. Evaluation of protein pigment epithelium–derived factor (PEDF) and microvessel density (MVD) as prognostic indicators in breast cancer. J Cancer Res Clin Oncol. 2010;136:1719–27.PubMedCrossRef Zhou D, Cheng SQ, Ji HF, et al. Evaluation of protein pigment epithelium–derived factor (PEDF) and microvessel density (MVD) as prognostic indicators in breast cancer. J Cancer Res Clin Oncol. 2010;136:1719–27.PubMedCrossRef
22.
go back to reference Bettencourt MC, Bauer JJ, Sesterhenn IA, Connelly RR, Moul JW. CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy. J Urol. 1998;160:459–65.PubMedCrossRef Bettencourt MC, Bauer JJ, Sesterhenn IA, Connelly RR, Moul JW. CD34 immunohistochemical assessment of angiogenesis as a prognostic marker for prostate cancer recurrence after radical prostatectomy. J Urol. 1998;160:459–65.PubMedCrossRef
23.
go back to reference Vartanian RK, Weidner N. Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am J Pathol. 1994;144:1188–94.PubMed Vartanian RK, Weidner N. Correlation of intratumoral endothelial cell proliferation with microvessel density (tumor angiogenesis) and tumor cell proliferation in breast carcinoma. Am J Pathol. 1994;144:1188–94.PubMed
24.
go back to reference Micalizzi DS, Christensen KL, Jedlicka P, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial–mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest. 2009;119:2678–90.PubMedCrossRef Micalizzi DS, Christensen KL, Jedlicka P, et al. The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial–mesenchymal transition and metastasis in mice through increasing TGF-beta signaling. J Clin Invest. 2009;119:2678–90.PubMedCrossRef
25.
go back to reference Yu M, Smolen GA, Zhang J, et al. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev. 2009;23:1737–42.PubMedCrossRef Yu M, Smolen GA, Zhang J, et al. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes Dev. 2009;23:1737–42.PubMedCrossRef
26.
go back to reference Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68:989–97.PubMedCrossRef Sarrió D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J. Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 2008;68:989–97.PubMedCrossRef
27.
go back to reference Ganapathy V, Ge R, Grazioli A, et al. Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer. 2010;9:122.PubMedCrossRef Ganapathy V, Ge R, Grazioli A, et al. Targeting the transforming growth factor-beta pathway inhibits human basal-like breast cancer metastasis. Mol Cancer. 2010;9:122.PubMedCrossRef
29.
go back to reference Millanta F, Lazzeri G, Vannozzi I, Viacava P, Poli A. Correlation of vascular endothelial growth factor expression to overall survival in feline invasive mammary carcinomas. Vet Pathol. 2002;39:690–6.PubMedCrossRef Millanta F, Lazzeri G, Vannozzi I, Viacava P, Poli A. Correlation of vascular endothelial growth factor expression to overall survival in feline invasive mammary carcinomas. Vet Pathol. 2002;39:690–6.PubMedCrossRef
30.
go back to reference Toi M, Kashitani J, Tominaga T. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer. 1993;55:371–4.PubMedCrossRef Toi M, Kashitani J, Tominaga T. Tumor angiogenesis is an independent prognostic indicator in primary breast carcinoma. Int J Cancer. 1993;55:371–4.PubMedCrossRef
31.
go back to reference Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.PubMedCrossRef Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324:1–8.PubMedCrossRef
32.
go back to reference Uzzan B, Nicolas P, Cucherat M, Perret GY. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 2004;64:2941–55.PubMedCrossRef Uzzan B, Nicolas P, Cucherat M, Perret GY. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 2004;64:2941–55.PubMedCrossRef
33.
go back to reference Borg A, Tandon AK, Sigurdsson H, et al. HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res. 1990;50:4332–7.PubMed Borg A, Tandon AK, Sigurdsson H, et al. HER-2/neu amplification predicts poor survival in node-positive breast cancer. Cancer Res. 1990;50:4332–7.PubMed
34.
go back to reference Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63:181–7.PubMedCrossRef Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63:181–7.PubMedCrossRef
35.
go back to reference Fisher B, Bauer M, Wickerham DL, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer. 1983;52:1551–7.PubMedCrossRef Fisher B, Bauer M, Wickerham DL, et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer. 1983;52:1551–7.PubMedCrossRef
36.
go back to reference Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956–62.PubMedCrossRef Ragaz J, Jackson SM, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997;337:956–62.PubMedCrossRef
Metadata
Title
HOXB9 Expression Promoting Tumor Cell Proliferation and Angiogenesis Is Associated with Clinical Outcomes in Breast Cancer Patients
Authors
Hirohito Seki, MD
Tetsu Hayashida, MD, PhD
Hiromitsu Jinno, MD, PhD
Shigemichi Hirose, MD, PhD
Michio Sakata, MD
Maiko Takahashi, MD
Shyamala Maheswaran, PhD
Makio Mukai, MD, PhD
Yuko Kitagawa, MD, PhD, FACS
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 6/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2295-5

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