AI Article Synopsis
- - The FOX family of transcription factors, including FOXN4, is linked to various diseases, particularly cancer, but the role of FOXN4 in breast cancer is not well understood.
- - This study found that higher levels of FOXN4 in normal breast tissue are associated with better outcomes in breast cancer; increasing FOXN4 reduces cancer cell growth and metastasis, while silencing it shows links to increased disease progression.
- - The research indicates that FOXN4 suppresses breast cancer growth by enhancing the activity of the tumor suppressor TP53 and inhibiting Notch signaling, suggesting the potential for clinical use of Notch inhibitors like PF-3084014 in breast cancer treatment.
Article Abstract
Objective: Fork head domain-containing transcription factor family (FOX), is comprised of >20 members. Members of FOX family have been implicated in a wide range of physiological and/or diseased conditions. Many of FOX members have been shown to be involved in tumorigenesis and progression. The potential roles in carcinogenesis of FOXN4, a member as one of the vast FOX family, remains relatively unknown.
Method: Here, we explored the potential involvement of FOXN4 in breast cancer.
Results: First, observed that a higher FOXN4 was identified in the normal adjacent breast tissue as compared to that in the breast cancer samples; an increased FOXN4 level was associated with a better prognosis in patients with breast cancer. In addition, ectopically expression of FOXN4 led to the decreased cell proliferation, reduced colony formation and metastatic abilities (EMT, migration and invasion) in breast cancer cell lines. Furthermore, we showed the direct interaction between FOXN4 and TP53 and FOXN4 binding led to the increased activity of TP53. Silencing FOXN4 led to reduced TP53 and increased expression of Dll4, Notch and survivin, providing a link between FOXN4 and Notch signaling. Finally, we used patient-derived xenograft mouse model to demonstrate the tumor inhibitory effects of Notch-inhibitor, PF-3084014. We found that PF-3084014 treatment led to a significantly smaller tumor burden and higher survival ratio in patient-derived xenograft mice as compared to the vehicle. This tumor suppressive effect was accompanied by the increased expression of TP53, FOXN4 and decreased Dll4 and Notch.
Conclusion: Collectively, our data strongly suggested the tumor suppressive roles of FOXN4 in breast tumorigenesis via the activation of TP53 while suppressing Notch signaling. Future studies are warranted to explore the clinical application of PF-3084104 (Notch inhibitor) for the treatment of breast cancer patients.
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| http://dx.doi.org/10.1016/j.gene.2019.144057 | DOI Listing |
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