Modeling Molecular Development Of Breast Cancer In Canine Mammary Tumors

Malignancy in cancer is a consequence of the progressive accumulation of mutations in a tumor, with profound implications for drug selection and treatment. However, in human studies, inter-patient variability obscures molecular signatures of tumor progression because patients usually present with a single mammary tumor. In contrast, dogs frequently exhibit multiple naturally occurring mammary tumors in the same individual. Moreover, canine mammary tumors (CMTs) and human breast cancer have similar histopathological profiles and clinical presentation. We leverage the CMT model to elucidate genome-wide molecular changes clinically relevant in human breast cancer, focusing on signals underlying tumor development. We develop a robust, generally applicable, computational analysis framework (FREYA) for analysis of CMTs for comparative oncology. Using FREYA, we RNA profile 89 samples from 16 dogs, and demonstrate that CMTs recapitulate human breast cancer subtypes. We then extract molecular profiles of breast cancer progression at three distinct stages (normal, pre-malignant and malignant) and identify signatures of gene expression reflective of tumor progression. Focusing on the transitions to malignancy, we identify transcriptional patterns and biological pathways specific to malignant tumors and distinct from those characterizing pre-malignant tumors or normal tissue. We find that human breast cancer patients whose tumors exhibit strong CMT malignancy signatures have significantly decreased survival, indicative of the importance of the tumor progression processes identified in CMTs to human breast cancer prognosis. Altogether, our comprehensive genomic characterization demonstrates that CMTs are a powerful translational model of breast cancer, providing insights that inform our understanding of tumor development in humans. To catalyze and support similar analyses and use of the CMT model by other biomedical researchers, we publicly share all of our data and provide FREYA, a robust data processing pipeline and statistical analyses framework, at freya.flatironinstitute.org. Citation Format: Kiley Graim, Dmitriy Gorenshteyn, David G. Robinson, Nicholas J. Carriero, James Cahill, Rumela Chakrabarti, Michael H. Goldschmidt, Amy C. Durham, Julien Funk, John D. Storey, Vessela N. Kristensen, Chandra L. Theesfeld, Karin U. Sorenmo, Olga G. Troyanskaya. Modeling molecular development of breast cancer in canine mammary tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2504.