Abstract 5221: Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression

Abstract

Abstract Despite evidence showing a positive correlation between angiogenesis and solid tumor progression, anti-angiogenic therapies have yielded limited, and often, tissue-specific responses. Whereas colorectal and renal cancers show improved responses, anti-angiogenic therapy has not proven effective at clinically managing breast tumor progression or prolonging patient survival. Moreover, anti-angiogenic treatment may promote the emergence of tumors with increased aggression and resistance to standard chemotherapies. Our laboratory has shown that sustained endothelial expression of the anti-angiogenic HoxA5 homeodomain transcription factor reduces angiogenesis and delays progression of squamous cell carcinoma in the KRT14-HPV16 mouse model of skin cancer. We subsequently investigated, whether constitutive endothelial expression of HoxA5 could also impede mammary tumor growth and metastasis. Surprisingly, we observed that endothelial HoxA5 expression increased both primary tumor growth and lung metastasis in the MMTV-PyMT mouse model of breast cancer. Primary tumors from PyMT/HoxA5+ mice exhibited an increased number of large vessels but were significantly more hypoxic, as compared to tumors from control mice. Orthotopic injection of isolated mammary tumor cells from PyMT/HoxA5+ mice into wild-type animals also resulted in larger tumors, as compared to tumor cells isolated from PyMT mice of the same age. Interestingly, although metastasis was increased in the PyMT/HoxA5+ transgenic mice, we did not detect differences in circulating tumor cells, suggesting that tumor cells from PyMT/HoxA5+ mice have increased tumor initiating potential. Thus, while anti-angiogenic HoxA5 expression in the endothelium delays skin tumor progression, more aggressive tumors arise in the mammary gland. We are currently evaluating the response of breast tumors in PyMT/HoxA5+ mice to standard cancer chemotherapeutics, as well as evaluating novel approaches to potentially target more aggressive tumors emerging from chronic hypoxic conditions. Citation Format: Josette Northcott, Hans Layman, Nancy Boudreau. Mammary tumor aggressiveness is exacerbated by endothelial HoxA5 expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5221. doi:10.1158/1538-7445.AM2015-5221