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

Lemler, David J.; Lynch, Miranda L.; Tesfay, Lia; Deng, Zhiyong; Paul, Bibbin T.; Wang, Xiaohong; Hegde, Poornima; Manz, David H.; Torti, Suzy V.; Torti, Frank M.

doi:10.1186/s13058-017-0814-9

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

Journal Article · 06 March 2017 · Breast Cancer Research

DOI: https://doi.org/10.1186/s13058-017-0814-9 · OSTI ID:1626928

Lemler, David J. ^[1]; Lynch, Miranda L. ^[2]; Tesfay, Lia ^[3]; Deng, Zhiyong ^[3]; Paul, Bibbin T. ^[3]; Wang, Xiaohong ^[3]; Hegde, Poornima ^[3]; Manz, David H. ^[3]; Torti, Suzy V. ^[3]; Torti, Frank M. ^[3]

Univ. of Connecticut, Farmington, CT (United States). Health Center; North Carolina State Univ., Raleigh, NC (United States); DOE/OSTI
Univ. of Connecticut, Farmington, CT (United States). Health Center; Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Univ. of Connecticut, Farmington, CT (United States). Health Center

Background: 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 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. Methods: The 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. Results: High 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. Conclusions: DCYTB 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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE; National Institute of Dental and Craniofacial Research (NIDCR); National Cancer Institute (NCI); National Institutes of Health (NIH)

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1626928

Journal Information:: Breast Cancer Research, Journal Name: Breast Cancer Research Journal Issue: 1 Vol. 19; ISSN 1465-542X

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
Oncology
DCYTB
Iron
Breast
Cancer
Prognosis
Survival
Cancer therapy
Focal adhesion