Abstract 3379: Iron-deficient anemia promotes breast cancer growth and lung metastasis

Abstract

Abstract Young breast cancer patients <45 years old are at a higher risk of dying from the disease than older patients. Specific risk factors contributing to this high mortality rate have not been identified. Iron deficient anemia (IDA) is a common ailment in young pre-menopausal women both in developed and developing countries. In the present study, we hypothesize that IDA promotes breast cancer growth and metastasis. To test this hypothesis, Balb/c mice were fed three levels of iron diets, 3.5 ppm Fe as iron deficient, 35 ppm as normal low, and 350 ppm as normal high for 12 wks. Consistent with previous literature reports, iron levels in diets ranging from 35 to 350 ppm, which were considered normal, did not lead to significant differences in serum iron and transferrin saturation rates. However, an iron level at 3.5 ppm in the diet caused an IDA in mice. After subcutaneously inoculating 4T1 mammary cancer cells into the flanks of mice fed different iron diets, mice with IDA condition have significant higher tumor volumes as compared to those with normal iron status (2922 + 161 mm3 in 3.5 ppm Fe group vs 1636 + 86 mm3 in 35 ppm Fe group and 1453 + 90 mm3 in 350 ppm Fe group). Lung metastasis was also higher in IDA mice with 22.8 + 0.9 nodules per lung lobule in 3.5 ppm vs 13.8 + 0.8 in 35 ppm and 13.6 + 0.9 in 350 ppm Fe. To elucidate molecular mechanisms of IDA in tumor growth and metastasis, levels of epithelial mesenchymal transition (EMT) markers, such as snail, slug and zeb1, were found to be significantly higher in tumor tissues isolated from IDA mice. When investigating signal pathways regulating EMT, it was found that Notch pathway, including Notch 2, 3, 4, and Notch ligands such as Jagged1, 2, were all induced by IDA. In contrast to Notch, transforming growth factor (TGF)-β and wingless-int (WNT) signal pathways, known to stimulate EMT, were not affected, suggesting that IDA-induced EMT is Notch pathway-specific. Since anemia causes hypoxia, the expression of HIF-1α, a key transcription factor controlling hypoxic responses, was also induced by IDA. Similarly, Notch signal pathway and EMT markers were higher after transfecting HIF-1α cDNA into 4T1 cells. These data show that IDA-mediated breast cancer growth and lung metastasis is through HIF-1α accumulation and activation of Notch and EMT. Our study suggests that identification of IDA as a poor prognostic factor and its clinical improvement as a potential cancer therapy could be significant to the high mortality rate of young breast cancer patients. This work is supported by R21 CA132684. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3379. doi:10.1158/1538-7445.AM2011-3379