DCYTB is a predictor of outcome in breast cancer that functions via iron-independent mechanisms

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0814-9) contains supplementary material, which is available to authorized users.

<p>Long Intergenic Non-Coding RNA 01121 Promotes Breast Cancer Cell Proliferation, Migration, and Invasion via the <em>miR-150-5p</em>/HMGA2 Axis</p>

“…4 However, the overall prognosis of breast cancer is still unsatisfactory due to recurrence and distant metastasis. 5 The proliferation and metastasis of breast cancer is a multi-step biological process that involves the activation or silencing of genes and epigenetic modifications; however, the details of its molecular mechanism are still largely unknown. 6 Therefore, further elucidation of the molecular mechanisms of breast cancer metastasis is urgently needed to provide the theoretical basis for improved breast cancer therapy.…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Tissue samples Highly expressed in esophageal adenocarcinoma compared with normal (49). High Dcytb expression was associated with increased survival of breast cancer patients (75).…”

“…Likewise, STEAP4 is also involved in trafficking, where its expression is induced by several cytokines and, thus, plays a role in inflammation, however, information regarding its role in cancer is vague (109). Dcytb reduction of ferric iron is important for absorption by duodenal enterocytes, but it has also been identified as a predictor of outcome and chemotherapy response for breast cancer patients (75). In conclusion, ferrireductases play an important role in iron uptake and in doing so contribute to cancer progression.…”

Elevated mRNA expression levels of DLGAP5 are associated with poor prognosis in breast cancer

“…The hazard ratios with 95% confidence interval and log-rank P-values were calculated using the KM plotter (26). GOBO (co.bmc.lu.se/gobo/), an online tool that contains 1,881 BC specimens, was used to identify genes that co-expressed with DLGAP5, and determine the clinical characteristics of DLGAP5 in patients with BC (27,28). Furthermore, GOBO also supports the applications of PAM50 gene expression subtype analysis, which is recognized as a prognostic gene signature assay by the National Comprehensive Cancer Network (29).…”