An Iron Regulatory Gene Signature in Breast Cancer: More than a Prognostic Genetic Profile?

Abstract

Miller LD, Coffman LG, Chou JW et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 71(21), 6728-6737 (2011). In breast cancer, recent progress in technology has enabled us to define different prognostic genetic signatures. Based upon them, breast tumors have been grouped into the four principal categories: basal-like or triple-negative, erbB2-positive, normal-like, and luminal type (A and B); with luminal types sharing the expression of estrogen receptor- and/or progesterone receptor-related genes and, basal-like and erbB2-positive subgroups associated with worse prognosis. So far, Oncotype DX(®) (Genomic Health Inc., Redwood City, CA, USA), Mammaprint(®) (Agendia Inc, Huntington Beach, CA, USA), the Breast Cancer Index(®) (BCI, Biotheranostics, San Diego, CA, USA) and PAM50 (Expression Analysis Inc., Durham, NC, USA) are the only multigene assays that have been marketed in North America and Europe. However, any genetic signature assay still has to gain acceptance as a validated assay before introduction into current clinical practice. This study describes an iron regulatory gene signature (IRGS) in breast cancer associated with clinical outcome. Within the molecular luminal type, the IRGS provides prognostic information similar to Oncotype DX and gene sets selected to assess proliferation. In spite of this, it is relevant that two complementary pathways that are regulatory of iron metabolism - the iron export (Fp/HAMP) and the iron import (TFRC/HFE) gene dyads - were embedded in the IRGS gene set and were associated with clinical outcome as well. Differences in metabolic pathways between cancer and normal cells have been widely described, and potential applications for more refined therapy have been proposed by expanding genetic signature assessment technology to concomitant metabolic pathways investigation. Consistent with this, it is reasonable to imagine that the iron-export and the iron-import gene dyads will be considered potential targets for treatment of breast cancer patients expressing the IRGS genes.

Pre-Clinical Insights into the Iron and Breast Cancer Hypothesis

“…Regarding disease pathogenesis and the effects of iron status on breast cancer, which is the focus of the work reported here, a review of the literature revealed that this topic appears to stimulate interest in cycles of roughly 10 years. A previous burst in published activity occurred in the timeframe of 2008–2013 [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The prevailing issues underlying those investigations included the impact of iron deficiency in limiting processes related to tumor development and the effects of excess iron-induced oxidative stress on the carcinogenic process.…”