Effects of Recombinant Erythropoietin on Breast Cancer-Initiating Cells

Abstract

Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

“…First, it may be interesting to determine whether the À235 polymorphism of survivin promoter affects erythropoiesis and favours erythrocemia. Secondly, as Epo is administered to breast cancer patients to prevent chemotherapy-induced anaemia during cancer treatment, it may be useful to check whether this treatment has no negative impact on the therapeutic control of breast cancer (Phillips et al, 2007) by increasing GATA-1 expression and downstream resistance genes such as survivin and bcl-xL.…”

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

“…In addition to the debate on Epo and EpoR characterization, an alternative biomolecular point of view might help to explain why EpoR is found both in the cytoplasm and bound to membrane [28], and to clinically explain why Epo may predict a negative impact on cancer control [16,30], suggesting physicians take into consideration the balance of the potential beneficial effects of Epo against a possible negative impact of this cytokine on a case-by-case basis [15,16].…”

“…In fact, the Epo protein was characterized as an intracellular glycoprotein in BC cell lines and tissues [17-19, 23-26, 40], and additionally found in breast secretions (i.e., milk and nipple aspirate fluid) [22,25]. Furthermore, biomolecular studies report that EpoR mRNA and protein were identified in BC cell lines and tumor tissues [18,19,23,27,40], whereas immunohistochemical studies localized EpoR in the cell cytoplasm [18,23,24,26] and also in tumor tissues as membrane-bound protein [16,17,24,26]. Interestingly, it has been demonstrated that BC cell lines may secrete the soluble fragment of EpoR peptide in conditioned medium, which may compete with membrane-bound receptor for ligand binding [19].…”

“…The Jigsaw Puzzle of Epo in Breast Cancer [16,30,52]. Even though many of the findings and conclusions of this matter are questionable because of problems with the methods used to detect the EpoR protein and to identify the spliced variants of the EpoR gene, the lack of appropriate controls, and the lack of detection of physiologically relevant surface EpoR on tumor cells, the fact that the erythropoietic and tissue effects of Epo are fostered through two distinct receptors (a homo-and heterodimer, respectively) with nonoverlapping functions raises the possibility of selective targeting of these activities by appropriate modulation of the two receptor systems.…”

“…Although the hypothetical mechanisms proposed here need to be supported/validated, they may project a different glimpse on all of the jigsaw pieces accumulated in the BC field, without either over-or underestimating any literature data. The two proposed biomolecular mechanisms (JAK-dependent and JAK-independent Epo-EpoR processing), in conjunction with the diverse biological availability of activated or cleaved EpoR, could provide an explanation why either endogenously produced (such as in inflammation and in cancer) or exogenously administered (such as in cancer-related anemia) Epo may promote, in some instances, tumor cell proliferation in BC-initiating cells [16], whereas, in other instances, it leads to better survival in BC patients [27]. Although our hypothesis actually provides more questions than answers, until the mechanisms of the contrasting literature data are resolved, the use and risks of Epo therapy should be carefully weighed, balancing the potential beneficial functions of Epo protecting tissues and ameliorating various anemias (including those associated with cancer) [11] against its detrimental effects, mainly linked to the tumor-promoting activity of Epo, a centenarian molecule yet to be fully disclosed [1,30,53,54].…”