Lactoferrin–Endothelin-1 Axis Contributes to the Development and Invasiveness of Triple-Negative Breast Cancer Phenotypes

• Published in: Cancer research (Chicago, Ill.) Vol. 71; no. 23; pp. 7259 - 7269
• Main Authors: Ha, Ngoc-Han, Nair, Vasudha S., Reddy, Divijendra Natha Sirigiri, Mudvari, Prakriti, Ohshiro, Kazufumi, Ghanta, Krishna Sumanth, Pakala, Suresh B., Li, Da-Qiang, Costa, Luis, Lipton, Allan, Badwe, Rajendra A., Fuqua, Suzanne, Wallon, Margaretha, Prendergast, George C., Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2011
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caco-2 Cells; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Down-Regulation; Endothelin A Receptor Antagonists; Endothelin-1 - genetics; Endothelin-1 - metabolism; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Female; Gynecology. Andrology. Obstetrics; Humans; Lactoferrin - antagonists & inhibitors; Lactoferrin - metabolism; Mammary gland diseases; Medical sciences; Neoplasm Invasiveness; Pharmacology. Drug treatments; Phenotype; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Receptor, Endothelin A - metabolism; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Receptors, Progesterone - genetics; Receptors, Progesterone - metabolism; RNA Processing, Post-Transcriptional - drug effects; Tumors; Drug; Breast disease; Pathophysiology; Endothelin 1; Malignant tumor; Metastasis; Research and development; Mammary gland diseases; Lactoferrin; Phenotype; Regulation(control); Tumor cell; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-1143

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. Cancer Res; 71(23); 7259–69. ©2011 AACR.