Abstract P4-07-07: HOXB9 Expression as a New Independent Prognostic Factor in Human Breast Cancer
Authors: Seki H , Hayashida T , Jinno H , Takahashi M , Sakata M , Hirose S , Mukai M , Kitagawa Y. 
Published: April 2011

Abstract
Background: There are several reports showing a HOX gene family, which plays the critical roles for the differentiation during the embryonic stage, is associated with the tumorigenicity. It was demonstrated that HOXB9 is overexpressed in 42% of breast cancers, specifically those with high histological grade, and we defined the functional consequences of elevated HOXB9 expression in breast cancer. Moreover, HOXB9 expression promotes increased neovascularization and tumor metastasis to the lung in mouse xenograft models (Hayashida et al., PNAS, 2010). The puropose of this report is to evaluate the correlation between HOXB9 and clinicopathological variables in breast cancer patients. Patients and methods: A consecutive series of 141 patients with invasive ductal carcinoma who underwent surgical treatment at Keio University Hospital from January 2004 to January 2005 was involved. HOXB9 expression was analyzed immunohistochemically on formalin-fixed, paraffin-embedded tumor sections using rabbit anti-human HOXB9polyclonal antibody. Moreover, immunohistochemical stainings for Ki-67, CD31, and CD34 were also performed to evaluate the association with HOXB9 expression.
Results: The age at the diagnosis ranged from 30 to 93 years (median age, 58 years), and median observation period was 62.2 months. Of 141 tumor specimens immunostained for HOXB9, 69 specimens (48.9%) were positive staining. Univariate logistic regression revealed ER negativity (P&lt;0.001), PR negativity (P&lt;0.001), HER2 positivity (p=0.031), high nuclear grade (P&lt;0.001) and large pathological tumor size (p=0.002) as significant variables associated with HOXB9 expression. Notably, 12 (92. 3%) out of 13 triple negative breast cancer showed HOXB9 expression. The disease-free survival (DFS) at 5 year and the overall survival at 5 year were significantly different between the HOXB9 positive group and HOXB9 negative group; HR=8.5, 95%CI 3.3-21.9, p=0.001, HR 3.8, 95%CI 1.5-9.6, p=0.003, respectively. A Multivariate analysis indicated that HOXB9 expression was the independent prognostic factor for DFS (HR=14.1, 95% CI 1.851 to 107.4, p=0.011). Since HOXB9 expression accelerates the tumor angiogenesis in vitro and in vivo, we also evaluated the expression of vascular endothelial marker, CD31 and CD34 and cellular proliferation marker, Ki-67 in 45 patients with clinical T2 (tumor size, 2 to 5cm) tumor. In this subgroup analysis, HOXB9 positive patients (n=22) showed increased number of vasculature and Ki-67 ratio in comparison with HOXB9 negative patients (n=23) with statistical significance.
Correlations between HOXB 9 expression and Ki-67, CD31 and CD 34
Conclusion: The data identify HOXB9 expression as a new independent prognostic factor in breast cancer, which might help to improve the selection for appropriate therapy. Possibly, it might be useful to determine the application of anti-angiogenic therapy.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-07-07.