Opposing effects of CRABP1 and CRABP2 homologs on the proliferation of breast cancer cells and their sensitivity to retinoic acid

Abstract

Resistance of tumor cells to retinoic acid (RA), a promising therapeutic agent, is the major factor limiting the use of RA in clinical practice. The mechanisms of RA resistance are still poorly understood. Cellular Retinoic Acid Binding Proteins, CRABP1 and CRABP2, are essential mediators of RA signaling, but the role of the two CRABP homologs in regulating cellular sensitivity to RA has not been well studied. In addition, the effects of CRABP1 and CRABP2 on cell proliferation have not been compared. Here, using a broad panel of breast cancer cell lines with different levels of RA sensitivity/resistance, we show for the first time that in RA-sensitive cells, CRABP1 expression is restricted by methylation and protein levels are highly variable. In moderately RA-resistant lines, a high level of CRABP1 is observed both at the mRNA and protein levels, unchanged by inhibition of DNA methylation. The maximally resistant cell lines are characterized by complete repression of CRABP1 implemented at transcriptional and posttranscriptional levels, and exogenous expression of each of CRABP homologs has no effect on the studied characteristics. CRABP1 and CRABP2 proteins have opposing effects on proliferation and sensitivity to RA. Specifically, in initially RA-sensitive cells CRABP1 stimulates and CRABP2 reduces proliferation and resistance to RA, while in more resistant cells the role of each homolog in both of these indications is reversed. Overall, we have shown for the first time that CRABP proteins exert different effects on the growth and sensitivity to RA of breast cancer cells (stimulation, suppression, or no effect) depending on the baseline level of RA-sensitivity, with the effects of CRABP1 and CRABP2 homologs on the studied properties always being opposite.