Ferroportin is an iron efflux pump that plays a key role in maintaining systemic body iron homeostasis. It is regulated by the peptide hormone hepcidin, which is made by the liver and circulates systemically. Ferroportin and hepcidin are central to assuring that iron delivery to the circulation is matched to systemic iron demand: mutations in ferroportin and hepcidin lead to inappropriate dietary iron uptake and retention, and result in hemochromatosis, a disease of iron overload. In the last grant cycle, we discovered that ferroportin and hepcidin are also manufactured in breast tissue, are essential to maintenance of iron homeostasis in the breast, and that disruption of this regulatory axis was a critical component of the transformed phenotype. In this application, we leverage these observations, as well as observations we made in the last grant period on how inflammatory, oncogenic and oxidative stress signals regulate ferreting, ferroportin and iron, to understand how iron trafficking and signaling are handled in the breast. We will explore the mechanistic link between disruptions of these regulatory circuits and their pathophysiological consequences. We will test whether blocking these pathways can modify disease progression in mouse models. We explore the fundamental iron biology that underpins these observations in three specific aims. We will explore (Aim 1) a novel autocrine and paracrine iron regulatory network in breast tissue that we recently uncovered, particularly the relationship and regulation of hepcidin and ferroportin by bone morphogenic proteins (BMPs) and their endogenous inhibitors. We will also study in detail the heretofore unrecognized transcriptional repression of ferroportin (Aim 2). Finally (Aim 3), we will address how classic systemic iron regulation mediated through liver- produced hepcidin interacts with this paracrine iron-regulatory axis in the breast. Taken together, we believe the proposed experiments break new ground by defining heretofore unknown pathways and new target tissues in the regulation of iron homeostasis and their link to disease.

Public Health Relevance

This proposal will allow us to better understand iron regulation in cells and tissues. We will specifically test whether interceding in iron-regulatory pathways can modify disease processes in breast tissue. Understanding these iron- regulatory networks is a critical first step to modifying these pathways for therapeutic benefit in a wide array of conditions, including cancer and inflammatory diseases such as arthritis, as well as the anemia that accompanies inflammation and chronic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA171101-26
Application #
8686792
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Salnikow, Konstantin
Project Start
1989-09-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
26
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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Manz, David H; Blanchette, Nicole L; Paul, Bibbin T et al. (2016) Iron and cancer: recent insights. Ann N Y Acad Sci 1368:149-61
Hatcher, Heather C; Tesfay, Lia; Torti, Suzy V et al. (2015) Cytoprotective Effect of Ferritin H in Renal Ischemia Reperfusion Injury. PLoS One 10:e0138505
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Tesfay, Lia; Clausen, Kathryn A; Kim, Jin Woo et al. (2015) Hepcidin regulation in prostate and its disruption in prostate cancer. Cancer Res 75:2254-63
Basuli, Debargha; Stevens, Richard G; Torti, Frank M et al. (2014) Epidemiological associations between iron and cardiovascular disease and diabetes. Front Pharmacol 5:117
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Wang, Wei; Deng, Zhiyong; Hatcher, Heather et al. (2014) IRP2 regulates breast tumor growth. Cancer Res 74:497-507
Torti, Suzy V; Torti, Frank M (2013) Cellular iron metabolism in prognosis and therapy of breast cancer. Crit Rev Oncog 18:435-48

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