Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Abstract

Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non–heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.

Intestinal Iron Homeostasis and Colon Tumorigenesis

“…Consistent with this data, iron content is increased in human colorectal tumors and tumors from mouse models of CRC compared to normal adjacent tissues as demonstrated by Prussian blue staining [64,68]. Similar alterations that result in increased iron acquisition and decreased iron export by the tumor are also observed for other tumors such as breast [69,70]. This data demonstrate that local iron requirements are increased in tumors compared to normal tissues, and the increase in intratumoral iron may be critical in tumor growth.…”

Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression

“…A growing number of studies were conducted to explore the role of iron-related proteins in the context of cancer [6, 7, 38]. The reduced expression of the iron exporter FPN in tumor cells was correlated to the aggressiveness of breast cancer subtypes [23]. High tumor cell FPN levels were correlated to other well-established prognostic markers for better patient survival and outcome, such as the absence of estrogen receptor, low histological grade, and low spread of disease to the lymph nodes.…”

“…Additionally, it was shown by the staining of iron deposits that the tumor outcompetes the natural iron reservoirs in liver and spleen [22]. Importantly, the expression levels of iron gene markers, particularly the iron exporter ferroportin, can be employed as independent predictors of prognosis in breast cancer [23] and might find important applications in individualized tumor therapy.…”

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

“…6,15−18 Furthermore, iron has been shown to contribute to tumor initiation and growth 15,19 and epidemiological evidence has established links between tumor iron metabolism and clinical outcomes in breast cancer patients. 17,20 Given that labile Fe(II) promotes Fenton chemistry, we sought to develop a tumor-targeting strategy in which Fenton reaction of a peroxidic prodrug was coupled to release of drug payloads. Recognizing that antimalarial agents such as arterolane 21−24 exhibit finely tuned iron(II) reactivity, 25−28 we subsequently developed 29,30 an arterolane-inspired small molecule platform (denoted TRX herein) for Fe(II)-dependent drug delivery.…”