Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study.

R Jordan Price,Karen A Lillycrop,Graham C Burdge

doi:10.1017/jns.2016.8

Abstract

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. To test this we investigated the effect of treatment with FA concentrations within the range of unmetabolised FA reported in humans on the expression of the transcriptome of non-transformed (MCF10A) and cancerous (MCF7 and Hs578T) BC cells. The total number of transcripts altered was: MCF10A, seventy-five (seventy up-regulated); MCF7, twenty-four (fourteen up-regulated); and Hs578T, 328 (156 up-regulated). Only the cancer-associated gene TAGLN was altered by FA in all three cell lines. In MCF10A and Hs578T cells, FA treatment decreased pathways associated with apoptosis, cell death and senescence, but increased those associated with cell proliferation. The folate transporters SLC19A1, SLC46A1 and FOLR1 were differentially expressed between cell lines tested. However, the level of expression was not altered by FA treatment. These findings suggest that physiological concentrations of FA can induce cell type-specific changes in gene regulation in a manner that is consistent with proliferative phenotype. This has implications for understanding the role of FA in BC risk. In addition, these findings support the suggestion that differences in gene expression induced by FA may involve differential activities of folate transporters. Together these findings indicate the need for further studies of the effect of FA on BC.

Highlights

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain
Folate receptor-α (FRα, FOLR1) expression has been shown to be increased in oestrogen receptor (ER) and progesterone receptor (PR) triple negative BC cells and is associated with poor prognosis[26], while RFCP has been shown to be differentially expressed in B-cell lymphoma[23]
Breast cancer cell lines exhibit differential expression of folate transporters The expression of SLC19A1 (RFCP) and SLC46A1 (PCFT), which are involved in the uptake of unmetabolised FA[22], and FOLR1 (FRα)(26), which has been linked to BC outcomes, were measured in MCF10A, MCF7 and Hs578T cell lines

Summary

Introduction

The effect of folic acid (FA) on breast cancer (BC) risk is uncertain. We hypothesised that this uncertainty may be due, in part, to differential effects of FA between BC cells with different phenotypes. In these three cell lines, 11/12 transcripts measured by quantitative RT-PCR had the same direction of change in expression as found with the microarray data (Table 2). Details of the differentially expressed transcripts from MCF10A, MCF7 and Hs578T cell lines are reported in Supplementary Tables S1, S2 and S3, respectively.

Results

Conclusion