Abstract
Vitamin D (VD) reduces the risk of breast cancer and improves disease prognoses. Potential VD analogs are being developed as therapeutic agents for breast cancer treatments. The large-conductance Ca2+-activated K+ channel KCa1.1 regulates intracellular Ca2+ signaling pathways and is associated with high grade tumors and poor prognoses. In the present study, we examined the effects of treatments with VD receptor (VDR) agonists on the expression and activity of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, flow cytometry, and voltage-sensitive dye imaging. Treatments with VDR agonists for 72 h markedly decreased the expression levels of KCa1.1 transcripts and proteins in MDA-MB-453 cells, resulting in the significant inhibition of depolarization responses induced by paxilline, a specific KCa1.1 blocker. The specific proteasome inhibitor MG132 suppressed VDR agonist-induced decreases in KCa1.1 protein expression. These results suggest that KCa1.1 is a new downstream target of VDR signaling and the down-regulation of KCa1.1 through the transcriptional repression of KCa1.1 and enhancement of KCa1.1 protein degradation contribute, at least partly, to the antiproliferative effects of VDR agonists in breast cancer cells.
Highlights
Breast cancer is the most common cancer in women, affecting more than two million women worldwide
Several studies reported VD receptor (VDR)-mediated responses in human breast cancer cell lines [4,5]. Concomitant with these findings, similar expression levels of VDR proteins at approximately 65 kDa were observed in the MDA-MB-453, YMB-1, and MCF-7 cells examined in the present study (Figure 1B)
The expression levels of ESR1 and ESR2 transcripts were originally very low in MDA-MB-453, and no changes were induced by the treatment with VDR agonists (Figure 6D,E). These results suggest that the modification of estrogen production and estrogen receptor (ER) expression may not be responsible for the VDR agonist-induced transcriptional regulation of KCa1.1 in breast cancer cells
Summary
Breast cancer is the most common cancer in women, affecting more than two million women worldwide. The multifunctional pro-hormone vitamin D (VD) and its metabolites activate transcriptional factor VR receptor (VDR)-mediated signaling [1]. The active vitamin D metabolite, 1α,25-dihydroxyvitamin D3 (calcitriol) regulates cell proliferation and differentiation in cancerous and non-cancerous cells [2,3]. VDR agonists such as calcitriol and its analogs have been shown to exert the potent antiproliferative effects in breast cancer cells [4,5]. Low serum levels of calcitriol are associated with the progression and a high incidence of triple negative breast cancer (TNBC), and VDR-positive breast cancer patients have significantly longer disease-free survival [6]. Recent studies have indicated: (1) a positive correlation between a VD deficiency and the risk of aggressive breast cancer; and (2) the inhibition of migration and invasion by VD analogs [5,7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
