Abstract
BackgroundDuodenal cytochrome b (DCYTB) is a ferrireductase that functions together with divalent metal transporter 1 (DMT1) to mediate dietary iron reduction and uptake in the duodenum. DCYTB is also a member of a 16-gene iron regulatory gene signature (IRGS) that predicts metastasis-free survival in breast cancer patients. To better understand the relationship between DCYTB and breast cancer, we explored in detail the prognostic significance and molecular function of DCYTB in breast cancer.MethodsThe prognostic significance of DCYTB expression was evaluated using publicly available microarray data. Signaling Pathway Impact Analysis (SPIA) of microarray data was used to identify potential novel functions of DCYTB. The role of DCYTB was assessed using immunohistochemistry and measurements of iron uptake, iron metabolism, and FAK signaling.ResultsHigh DCYTB expression was associated with prolonged survival in two large independent cohorts, together totaling 1610 patients (cohort #1, p = 1.6e-11, n = 741; cohort #2, p = 1.2e-05, n = 869; log-rank test) as well as in the Gene expression-based Outcome for Breast cancer Online (GOBO) cohort (p < 1.0e-05, n = 1379). High DCYTB expression was also associated with increased survival in homogeneously treated groups of patients who received either tamoxifen or chemotherapy. Immunohistochemistry revealed that DCYTB is localized on the plasma membrane of breast epithelial cells, and that expression is dramatically reduced in high-grade tumors. Surprisingly, neither overexpression nor knockdown of DCYTB affected levels of ferritin H, transferrin receptor, labile iron or total cellular iron in breast cancer cells. Because SPIA pathway analysis of patient microarray data revealed an association between DCYTB and the focal adhesion pathway, we examined the influence of DCYTB on FAK activation in breast cancer cells. These experiments reveal that DCYTB reduces adhesion and activation of focal adhesion kinase (FAK) and its adapter protein paxillin.ConclusionsDCYTB is an important predictor of outcome and is associated with response to therapy in breast cancer patients. DCYTB does not affect intracellular iron in breast cancer cells. Instead, DCYTB may retard cancer progression by reducing activation of FAK, a kinase that plays a central role in tumor cell adhesion and metastasis.
Highlights
Duodenal cytochrome b (DCYTB) is a ferrireductase that functions together with divalent metal transporter 1 (DMT1) to mediate dietary iron reduction and uptake in the duodenum
DCYTB as a prognostic indicator of breast cancer Expression of DCYTB predicts metastasis/relapse-free survival We first examined the prognostic significance of DCYTB when considered as a single gene rather than as part of the larger iron regulatory gene signature (IRGS) gene signature [32]
Analysis of the combined cohort of 741 breast cancer patients that was used in the design of the IRGS [32], revealed that high DCYTB expression was an excellent overall predictor of distant metastasis-free survival (p = 1.6e-11, n = 741, log-rank test; Fig. 1a)
Summary
Duodenal cytochrome b (DCYTB) is a ferrireductase that functions together with divalent metal transporter 1 (DMT1) to mediate dietary iron reduction and uptake in the duodenum. Iron can act as a tumor growth factor, potentiating the growth of numerous tumors, including breast tumors, in animal models [2, 3]. Consistent with these laboratory studies, epidemiologic studies have linked excess iron and cancer [4,5,6,7]. The major mechanism of iron import in both normal and malignant cells is the transferrin/transferrin receptor endocytic pathway. Other mechanisms of iron import include uptake of heme, ferritin, and import of siderophore-bound iron by proteins such as the secreted glycoprotein Lipocalin 2 (LCN2, NGAL), [12,13,14,15]
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