Abstract
Background: Several studies have shown that cancer incidence is increasing in patients with chronic heart failure. We have reported that nerve growth factor (NGF) plays a pivotal role in sympathetic nerve remodeling after myocardial infarction (MI). However, the impact of NGF on cancer progression in the setting of MI-induced heart failure remains to be elucidated. Methods and Results: NGF phosphorylated tropomyosin receptor kinase A (TrkA) in murine breast carcinoma 4T1 cells, and NGF increased the percentage of Ki-67 positive 4T1 cells. MI was induced by permanent ligation of the left anterior descending artery of female Balb/c mice. Then, 4T1 cells were injected into the right fourth mammary fat pad at two weeks after MI surgery. Serum levels of NGF were higher in the MI group than in the sham group at the time of 4T1 cell injection (279±107 pg/ml vs. 172±36 pg/ml, P=0.014). The size of breast cancer was significantly larger in the MI group than in the sham group at three weeks after 4T1 cell injection (451.8±137 mm 3 vs. 304.3±136 mm 3 , P=0.0014, figure). The percentage of Ki-67 positive cells in cancer tissue was higher in the MI group compared to the sham group (37.1±6.8% vs. 16.5±3.2%, P<0.001). Furthermore, membranous TrkA was more phosphorylated in the MI group than in the sham group (1.56±0.11 AU vs. 1.00±0.11 AU, P<0.001). Knockdown of TrkA with siRNA in 4T1 cells suppressed the increase of Ki-67 positive cells by NGF stimulation (51.9±1.2% vs. 24.9±3.7%, P=0.044). A TrkA inhibitor, GW441756, suppressed the NGF-induced phosphorylation of TrkA in 4T1 cells. Moreover, the percentage of Ki-67 positive cells in cancer tissue was lower in the MI mice treated with a TrkA inhibitor (10 mg/kg/week, I.P.) than in the MI mice without a TrkA inhibitor (26.3±3.6% vs. 45.6±3.7%, P<0.001). Conclusion: Increased NGF caused by MI is associated with breast cancer progression through NGF/TrkA axis.
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