Effect of all-trans-retinoic acid on c-fins proto-oncogene [colony-stimulating factor 1 (CSF-1) receptor] expression and CSF-1-induced invasion and anchorage-independent growth of human breast carcinoma cells

Abnormal expression of c-fins proto-oncogene, which encodes for the macroph age colony-stimulating factor-1 (CSF-1) receptor, has been observed in a va riety of carcinomas of epithelial origin, including those of the breast. He re, we have investigated the effect of retinoic acid (RA), an important reg ulator of normal differentiation of mammary epithelial tissues, on the expr ession of the c-fms gene and CSF-1/CSF-1 receptor-induced invasion and anch orage-independent growth in breast carcinoma cells. We have demonstrated th at all-trans-Rn (atRA) significantly increases levels of c-fms transcripts in the estrogen receptor-negative but RA receptor alpha-positive breast car cinoma cell lines BT20 and SKBR3. The atRA-induced increase in fms transcri pt levels was completely abolished by RO41-5253, a synthetic RA receptor a! antagonist. Our results indicate that atRA could enhance fms expression by up-regulating the activity of the first promoter of the fms gene. DNase I protection, mobility shift; and mutational analysis revealed that a potenti al activator protein 1 (AP-I) site in the first fms promoter sequence could mediate the observed atRA effect on fms transcription. Our results also sh owed that atRA, by itself and in the presence of CSF-1, can increase the ab ility of breast carcinoma cells to invade is vitro. Furthermore, we demonst rated that atRA is able to abolish the CSF-1-induced increase in anchorage- independent growth of breast carcinoma cells without affecting the anchorag e-dependent growth, In summary, our findings suggest that retinoids may pla y conflicting roles throughout breast cancer progression, depending on the stage of cancer development. Although retinoids might suppress growth at th e early stages of tumor formation, they might promote malignant transformat ion at later stages by stimulating the invasive capacity of certain cell va riants in the breast tumor population.