Calcitriol Inhibits the Proliferation of Triple-Negative Breast Cancer Cells through a Mechanism Involving the Proinflammatory Cytokines IL-1βand TNF-α

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive tumors, with poor prognosis and high metastatic capacity. The aggressive behavior may involve inflammatory processes characterized by deregulation of molecules related to the immunological responses in which interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) are involved. It is known that calcitriol, the active vitamin D metabolite, modulates the synthesis of immunological mediators; however, its role in the regulation of IL-1βand TNF-αin TNBC has been scarcely studied. In the present study, we showed that TNBC cell lines SUM-229PE and HCC1806 expressed vitamin D, IL-1β, and TNF-αreceptors. Moreover, calcitriol, its analogue EB1089, IL-1β, and TNF-αinhibited cell proliferation. In addition, we showed that synthesis of both IL-1βand TNF-αwas stimulated by calcitriol and its analogue. Interestingly, the antiproliferative activity of calcitriol was significantly abrogated when the cells were treated with anti-IL-1βreceptor 1 (IL-1R1) and anti-TNF-αreceptor type 1 (TNFR1) antibodies. Furthermore, the combination of calcitriol with TNF-αresulted in a greater antiproliferative effect than either agent alone, in the two TNBC cell lines and an estrogen receptor-positive cell line. In summary, this study demonstrated that calcitriol exerted its antiproliferative effects in part by inducing the synthesis of IL-1βand TNF-αthrough IL-1R1 and TNFR1, respectively, in TNBC cells, highlighting immunomodulatory and antiproliferative functions of calcitriol in TNBC tumors.

Interleukin-1β and Cancer

“…Using the cancer genome atlas (TCGA) database, breast cancer patients with high levels of mRNA expression of IL1B were shown to have a better prognosis than those with low levels [ 30 ]. Similarly, the quantification of IL1B mRNA by qPCR in cervical cancer biopsies showed an increase in the risk of progression of pre-neoplasic lesions in women with lower IL1B expression [ 31 ].…”

Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

“…On the other hand, 1,25(OH)2D modulates the synthesis of immunological mediators [65]. It was shown that 1,25(OH)2D and its analogue, EB1089, inhibited proliferation of the TNBC cell lines SUM-229PE and HCC1806 that expressed VDR, IL-1β, and TNF-α receptors [66]. These studies also showed that synthesis of IL-1β and TNF-α was stimulated by 1,25(OH)2D and EB1089.…”

Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells

“…Moreover, the co-treatment with 1,25(OH) 2 D and TNF-α inhibited metalloprotease-9 (MMP-9) and monocyte chemoattractant protein-1 (MCP-1) protein expression, otherwise hyperactivated in presence of TNF-α alone, by demonstrating a further role of vitamin D in the regulation of infiltration, migration and cancer invasiveness [174]. Conversely, human breast cancer cells treated with 1,25(OH) 2 D showed decreased proliferation, in part induced by the reduced TNF-α and IL-1β synthesis, by demonstrating that even drastic deregulation of immune modulators may contribute to cancer progression [137].…”

“…Anticancer activity of vitamin D has been largely studied in different types of tumors, elucidating its pivotal role in cancer progression and invasion [ 134 ]. It has been reported that vitamin D inhibits colorectal, prostate and breast cancer cells growth by controlling cell proliferation [ 11 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ] through cell cycle arrest [ 144 , 147 , 148 , 149 , 150 ], by regulating cell death through apoptosis [ 54 , 144 , 147 , 151 , 152 , 153 ] and autophagic processes [ 154 , 155 ], and by modulating inflammatory processes implicated in immune infiltration and tumor invasiveness [ 134 , 137 , 150 ].…”