UNLABELLED: Heart failure and cancer are the leading cause of deaths worldwide. While heart failure and cancer have been considered separate diseases, it is becoming evident that they are highly connected and affect each other's outcomes. Recent studies using experimental mouse models have suggested that heart failure promotes tumor progression. The mouse models used involve major irreversible surgery. Here, we induced heart hypertrophy via expression of activating transcription factor 3 (ATF3) in cardiomyocytes, followed by cancer cells' implantation. Tumors developing in ATF3-transgenic mice grew larger and displayed a more highly metastatic phenotype compared with tumors in wild-type mice. To address whether ATF3 expression or the cardiac outcome are necessary for tumor progression, ATF3 expression was turned off after cardiac hypertrophy development followed by cancer cell implantation. The tumor promotion phenotype and the enhancement of metastatic properties were preserved, suggesting that the failing heart per se is sufficient to promote tumor progression. Serum derived from ATF3-transgenic mice enhanced cancer cell proliferation and increased cancer cell metastatic properties in vitro. Using a cytokine array panel, multiple factors responsible for promoting tumor cell proliferation and the metastatic phenotype were identified. Interestingly, the failing heart and the tumor separately and simultaneously contributed to higher levels of these factors in the serum as well as other tissues and organs. These data suggest the existence of intimate cross-talk between the hypertrophied heart and the tumor that is mediated by secreted factors, leading to cancer promotion and disease deterioration. SIGNIFICANCE: This work highlights the importance of early diagnosis and treatment of heart failure prior to reaching the irreversible stage that can exacerbate cancer progression.