title: Lactoferrin-endothelin-1 axis contributes to the development and invasiveness of triple-negative breast cancer phenotypes.
abstract: Triple-negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor-α (ER-α), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). However, pathways responsible for downregulation of therapeutic receptors, as well as subsequent aggressiveness, remain unknown. In this study, we discovered that lactoferrin (Lf) efficiently downregulates levels of ER-α, PR, and HER-2 in a proteasome-dependent manner in breast cancer cells, and it accounts for the loss of responsiveness to ER- or HER-2-targeted therapies. Furthermore, we found that lactoferrin increases migration and invasiveness of both non-TNBC and TNBC cell lines. We discovered that lactoferrin directly stimulates the transcription of endothelin-1 (ET-1), a secreted proinvasive polypeptide that acts through a specific receptor, ET(A)R, leading to secretion of the bioactive ET-1 peptide. Interestingly, a therapeutic ET-1 receptor-antagonist blocked lactoferrin-dependent motility and invasiveness of breast cancer cells. The physiologic significance of this newly discovered Lf-ET-1 axis in the manifestation of TNBC phenotypes is revealed by elevated plasma and tissue lactoferrin and ET-1 levels in patients with TNBC compared with those in ER(+) cases. These findings describe the first physiologically relevant polypeptide as a functional determinant in downregulating all three therapeutic receptors in breast cancer, which uses another secreted ET-1 system to confer invasiveness. Results presented in this article provide proof-of-principle evidence in support of the therapeutic effectiveness of ET-1 receptor antagonist to completely block the lactoferrin-induced motility and invasiveness of the TNBC as well as non-TNBC cells, and thus, open a remarkable opportunity to treat TNBC by targeting the Lf-ET-1 axis using an approved developmental drug.
authors: Department of Biochemistry and Molecular Biology and Global Cancer Genomic Consortium, The George Washington University, Washington, District of Columbia 20037, USA.
authors: Ngoc-Han
authors: NH
authors: Ha
authors: Vasudha S
authors: VS
authors: Nair
authors: Divijendra Natha Sirigiri
authors: DN
authors: Reddy
authors: Prakriti
authors: P
authors: Mudvari
authors: Kazufumi
authors: K
authors: Ohshiro
authors: Krishna Sumanth
authors: KS
authors: Ghanta
authors: Suresh B
authors: SB
authors: Pakala
authors: Da-Qiang
authors: DQ
authors: Li
authors: Luis
authors: L
authors: Costa
authors: Allan
authors: A
authors: Lipton
authors: Rajendra A
authors: RA
authors: Badwe
authors: Suzanne
authors: S
authors: Fuqua
authors: Margaretha
authors: M
authors: Wallon
authors: George C
authors: GC
authors: Prendergast
authors: Rakesh
authors: R
authors: Kumar
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007781:Lactoferrin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D044022:Receptor, Endothelin A / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D047628:Estrogen Receptor alpha; D007781:Lactoferrin; D046988:Proteasome Endopeptidase Complex; D044022:Receptor, Endothelin A; D018719:Erb-b2 Receptor Tyrosine Kinases; D011980:Receptors, Progesterone; C506487:ESR1 protein, human; C508053:ERBB2 protein, human