Abstract 12858: Myocardial Infarction Promotes Breast Cancer Growth Through the Nerve Growth Factor/Tropomyosin Receptor Kinase A Pathway

Abstract

Background: Epidemiological studies have suggested that patients with heart failure due to myocardial infarction (MI) have a higher cancer incidence. Nerve growth factor (NGF) plays a pivotal role in sympathetic nerve remodeling after MI, but several studies have suggested that NGF also plays a significant role in cancer progression. However, the impact of NGF on cancer progression in the setting of MI remains to be elucidated. Methods and Results: MI was induced by permanent ligation of the left anterior descending artery in female BALB/c mice. 4T1 cells, mammary tumor cells, were injected into the right mammary fat pad 2 weeks after surgery. Levels of NGF expression in the myocardium 3 days after surgery (1.40±0.17 AU vs. 1.00±0.09 AU, P=0.049) and serum NGF at 2 weeks after surgery (279±34 pg/ml vs. 173±16 pg/ml, P=0.044) were higher in the MI group than in the sham group. In addition, the tumor volume was significantly larger in the MI group than in the sham group 3 weeks after 4T1 cell injection (465.3±32.6 mm 3 vs. 292.1±28.3 mm 3 , P<0.001). The percentage of Ki67-positive cells in tumor tissue was higher in the MI group than in the sham group (37.1±5.7% vs. 16.5±3.6%, P=0.010). Moreover, phosphorylation activities of membranous tropomyosin receptor kinase A (TRKA, 1.54±0.04 AU vs. 1.00±0.09 AU, P<0.001) and AKT (1.56±0.18 AU vs. 1.00±0.08 AU, P=0.046) were higher in the MI group than in the sham group. Inhibition of TRKA by a TRKA inhibitor, GW441756 (20 mg/kg/week, I.P.), suppressed tumor volume in MI mice compared to DMSO-treated MI mice (281.6±34.8 mm 3 vs. 443.9±50.8 mm 3 , P<0.001). The percentage of Ki67-positive cells (31.9.1±2.8% vs. 42.2±2.0%, P=0.010), phosphorylation levels of TRKA (0.99±0.07 AU vs. 1.68±0.09 AU, P<0.001) and AKT (0.90±0.01 AU vs. 1.19±0.05 AU, P=0.001) in tumor tissues were decreased in GW441756-treated MI mice than in DMSO-treated MI mice. Conclusion: The NGF/TRKA pathway is involved in accelerated tumor cell growth under MI-induced heart failure.