Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta

Abstract

Breast cancer is the most common malignancy in women and the appearance of distant metastases produces the death in 98% of cases. The retinoic acid receptor β (RARβ) is not expressed in 50% of invasive breast carcinoma compared with normal tissue and it has been associated with lymph node metastasis. Our hypothesis is that RARβ protein participates in the metastatic process. T47D and MCF7 breast cancer cell lines were used to perform viability assay, immunobloting, migration assays, RNA interference and immunofluorescence. Administration of retinoic acid (RA) in breast cancer cells induced RARβ gene expression that was greatest after 72 hrs with a concentration 1 μM. High concentrations of RA increased the expression of RARβ causing an inhibition of the 60% in cell migration and significantly decreased the expression of migration-related proteins [moesin, c-Src and focal adhesion kinase (FAK)]. The treatment with RARα and RARγ agonists did not affect the cell migration. On the contrary, the addition of the selective retinoid RARβ-agonist (BMS453) significantly reduced cell migration comparable to RA inhibition. When RARβ gene silencing was performed, the RA failed to significantly inhibit migration and resulted ineffective to reduce moesin, c-Src and FAK expressions. RARβ is necessary to inhibit migration induced by RA in breast cancer cells modulating the expression of proteins involved in cell migration.

Emerging functional roles of nuclear receptors in breast cancer

“…Specifically, all-trans retinoid acid (ATRA) was reported to modulate several migration-related proteins such as downregulation of MMP-1, MMP-2, MMP-9, FAK, NF-κB and p-ERK and upregulation of E-cadherin in breast cancer cell lines (Liu et al 2003, Dutta et al 2009. The anti-migratory effect of retinoids on breast cancer cells were shown to be mediated through RARB with treatment of RA or RARB agonist resulting in significantly reduced cell migration while treatment with RARA or RARG agonists did not (Flamini et al 2014). RARB is the only member of the RARs showing decreased expression in breast cancers (Muscat et al 2013).…”

“…A number of other nuclear receptors, including the vitamin D3 receptor (VDR) (Krishnan et al 2010, Mehta et al 2013) and the glucocorticoid receptor (GR) (Vilasco et al 2011, Abduljabbar et al 2015b have also been investigated for their anti-proliferative and anti-apoptotic effects in breast cancer. Members of the retinoid receptor subfamily have also received considerable attention, particularly the crosstalk between the retinoic acid receptor alpha (RARA) and estrogen signaling (Hua et al 2009, Ross-Innes et al 2010, and the anti-migratory effect of the retinoic acid receptor beta (RARB) in breast cancer (Yang et al 2002, Flamini et al 2014. However, the functional roles of the majority of the remaining members of the human NR family in the normal breast and breast cancer have largely been unexplored.…”

All-Trans Retinoic Acid Inhibits Migration and Invasiveness of Rheumatoid Fibroblast-Like Synoviocytes

“…In addition, retinoids have been considered for the treatment of several types of cancer and autoimmune diseases. In cancer cells, retinoids induce differentiation, cell cycle arrest, apoptosis, and inhibition of cell migration and invasiveness (Flamini et al, 2014;Young et al, 2015;Cui et al, 2016;Li et al, 2017). In autoimmune diseases, retinoids have shown improvement of animal models of multiple sclerosis (Massacesi et al, 1991), systemic lupus erythematosus (Perez de Lema et al, 2004), type 1 diabetes , and RA (Kuwabara et al, 1996;Kwok et al, 2012).…”

A comparative study of protein patterns of human estrogen receptor positive (MCF-7) and negative (MDA-MB-231) breast cancer cell lines

“…Within 30 proteins detected in estrogen receptor-negative MDA-MB-231 cells, moesin plays a marked role in the cancer cell invasiveness and pattern of metastasis characteristic of estrogen receptor-negative breast cancers (Carmeci et al 1998). All-trans retinoic acid acting through nuclear retinoid receptors was found to increase the expression of all-trans retinoic acid receptor beta causing an inhibition of the 60% in cell migration and significantly decreases the expression of moesin and other migration-related proteins (Flamini et al 2014).…”