Breast Tumor Microenvironment Shapes Vascular Response To Endothelial Hoxa5 Expression

Current anti-angiogenic therapy for the treatment of solid tumors is based on directed inhibition of growth factor signaling pathways essential for the development of new blood vessels. Despite evidence showing a positive correlation between angiogenesis and breast cancer progression, existing anti-angiogenic therapies have not proven effective at clinically managing breast tumors or prolonging patient survival. Several studies have shown that tissue microenvironment shapes local angiogenic responses and tumor progression - a finding that may partially explain the refractoriness of breast tumors to anti-angiogenic therapy. Data from our laboratory supports an anti-angiogenic role for the HoxA5 homeodomain containing transcription factor. Using the KRT14-HPV16 mouse model of skin cancer crossed with our tetracycline-regulated mouse line that expresses HoxA5 in the endothelium, we observed that HoxA5 reduced angiogenesis and slowed tumor progression in the skin. Thus, we hypothesized that constitutive endothelial expression of HoxA5 during mammary tumor development would prevent tumor growth and metastasis via modulation of the endothelial phenotype. Surprisingly, in the MMTV-PyMT mouse model of breast cancer, we observed that endothelial HoxA5 expression increased both primary tumor growth and lung metastasis. Mammary tumors from PyMT/HoxA5+ mice had larger areas of hypoxia and necrosis, as compared to primary tumors from control mice. Although we did not detect any change in intra-tumoral vascular staining (CD31+), we observed an increased number of large vessels and reduced vascular leakage in the primary tumors from PyMT/HoxA5+ mice. In contrast, subcutaneous injection of MMTV-PyMT mammary tumor cells into HoxA5 transgenic mice displayed significantly reduced tumor growth and decreased intra-tumoral vascularization, as compared to controls. This suggests that, unlike the anti-angiogenic properties of HoxA5 in the skin microenvironment, within the context of the mammary gland HoxA5 has vascular normalization effects. We conclude that the tissue microenvironment shapes the vascular response to anti-angiogenic agents and thereby controls tumor progression. Citation Format: Josette Northcott, Ileana Cuevas, Hans Layman, Nancy Boudreau. Breast tumor microenvironment shapes vascular response to endothelial HoxA5 expression. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A07. doi:10.1158/1538-7445.CHTME14-A07