التفاصيل البيبلوغرافية
| العنوان: |
Lactoferrin-Endothelin-1 Axis Contributes to the Development and Invasiveness of Triple-Negative Breast Cancer Phenotypes. |
| المؤلفون: |
Ngoc-Han Ha1, Nair, Vasudha S.1, Reddy, Divijendra Natha Sirigiri1, Mudvari, Prakriti1, Ohshiro, Kazufumi1, Ghanta, Krishna Sumanth1, Pakala, Suresh B.1, Da-Qiang Li1, Costa, Luis2,3, Lipton, Allan4, Badwe, Rajendra A.2,5, Fuqua, Suzanne6, Wallon, Margaretha7, Prendergast, George C.7, Kumar, Rakesh1,2 |
| المصدر: |
Cancer Research. Dec2011, Vol. 71 Issue 23, p7259-7269. 11p. |
| مصطلحات موضوعية: |
*LACTOFERRIN, *ENDOTHELINS, *CANCER invasiveness, *TRIPLE-negative breast cancer, *ESTROGEN receptors, *PROGESTERONE receptors, *HER2 protein, *PROTEASOMES |
| مستخلص: |
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, pathway 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 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. [ABSTRACT FROM AUTHOR] |
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