The Role of Lactoferrin in Breast Cancer Progression Open Access
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Triple-negative breast cancer is characterized by loss of ER alpha, PR and HER2 receptors and hence, lack of responsiveness to therapies targeting these receptors. However, the nature of endogenous molecules/pathways that might be responsible for the loss of three therapeutic receptor targets and thus, progression of breast cancer remains unknown. Clinical studies have shown that there is an increased risk for basal-like breast cancer in young women at first full term pregnancy. Since lactoferrin is a major milk protein, we explored the relationship between the levels of these receptors and the lactoferrin, an iron-binding ubiquitous protein with multiple functions. Here we discovered that lactoferrin efficiently downregulates the levels of ER alpha, PR and HER2 receptors in a proteosome-dependent manner in multiple ER+ or HER2+ breast cancer cells, and leads to the loss of responsiveness to HER2- or ER-targeted therapies and increased invasiveness of lactoferrin-stimulated cells; in contrast, TNBC cell lines were inherently invasive in response to lactoferrin. To understand the mechanism underlying of lactoferrin-mediated invasiveness of breast cancer cells, we used microarray chip hybridization approach to identify lactoferrin-regulated genes, and identified endothelin-1 (ET-1), a secreted pro-invasive polypeptide that acts through a specific receptor ET(A)R, as lactoferrin-regulated gene in multiple breast cancer cell lines. We found that lactoferrin directly binds to specific iron-binding consensus motifs in the ET-1 promoter and stimulates its transcription, leading secretion of bioactive endothelin-1 peptide. Interestingly, a therapeutic ET-1 receptor antagonist drug completely blocked lactoferrin-dependent motility and invasiveness of non-TNBC and TNBC cells. To establish the physiologic significance of this newly discovered lactoferrin-ET-1 axis in the development and manifestation of TNBC phenotypes, we found evidence of elevated serum levels of lactoferrin and ET-1 as well as co-upregulation of lactoferrin and ET-1 in tumor tissues from TNBC patients as compared to the levels in ER+ breast cancer patients, suggesting a potential causal association of lactoferrin with TNBC phenotypes and associated invasiveness, presumably, due to transcriptional stimulation of ET-1. These findings describe the first physiologically relevant polypeptide as a determinant of downregulating all three therapeutic receptors in breast cancer which utilizes another secreted ET-1 system to confer invasive TNBC phenotypes. Since a number of approved drugs targeting ET-1 system are in non-cancer clinical trials, these studies raise the possibility of targeting lactoferrin-ET-1 axis to delay and/or reverse the progression of clinical features of TNBC patients.