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Breast Cancer

Erythropoietin and Its Receptor in Breast Cancer: Putting Together the Pieces of the Puzzle

Department of Biomolecular Sciences, Section of Clinical Biochemistry, University "Carlo Bo," Urbino, Italy

Key Words. Erythropoietin • Erythropoietin receptor • Breast cancer • JAK2 signaling • Epo–EpoR homo- and heterodimeric complex • Cancer-related anemia

Correspondence: Ferdinando Mannello, Ph.D., D.Sc., Sezione di Biochimica Clinica del Dipartimento di Scienze Biomolecolari, Università Studi "Carlo Bo," Via O. Ubaldini 7, 61029 Urbino (PU), Italy. Telephone:39-0722-351479; Fax: 39-0722-322370; e-mail: ferdinando.mannello{at}uniurb.it

Received May 5, 2008; accepted for publication June 5, 2008; first published online in THE ONCOLOGIST Express on July 2, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

The expression of erythropoietin (Epo) and the Epo receptor (EpoR) has been detected in healthy tissue as well as in a variety of human cancers, including breast. Functional Epo/EpoR signaling in cancer cells, which contributes to disease initiation/progression, is not completely straightforward and is difficult to reconcile with the clinical practice of preventing/treating anemia in cancer patients with recombinant Epo. Preclinical and clinical investigations have provided contrasting results, ranging from a beneficial role that improves the patient's overall survival to a negative impact that promotes tumor growth progression. A careful gathering of Epo/EpoR biomolecular information enabled us to assemble an unexpected jigsaw puzzle which, via distinct JAK-dependent and JAK-independent mechanisms and different internalization/recycling as well as ubiquitination/degradation pathways, could explain most of the controversies of preclinical and clinical studies. However, until the mechanisms of the contrasting literature data are resolved, this new point of view may shed light on the Epo/EpoR paracrine/autocrine system and function, providing a basis for further studies in order to achieve the highest possible benefit for cancer patients.

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