The relationship of cellular retinoid metabolism to cellular growth inhibition in normal human and carcinogenic mammary cell lines

Retinoids are known to regulate cellular growth and differentiation and have been shown to have chemopreventive effects against breast and other cancers. Retinoic acid (RA) is the primary endogenous vitamin A metabolite responsible for these biological effects. These effects are thought to be mediated through gene modulation.; We suggest that breast cancer cells may not metabolically produce adequate amounts of RA to control cellular growth and differentiation. The experiments in this thesis are designed to address this hypothesis.; In the first and second studies we characterized ROH metabolism in terms of RA and retinyl ester production in normal mammary epithelial cells (HMECs) and two carcinogenic mammary cell lines, MCF-7 cells, which are estrogen receptor positive (ER+) and MDA MB-231 cells, which are (ER−), and ascertained whether the synthesis of metabolites was related to cellular growth responsiveness. We found that the normal HMECs were the most active metabolically, producing both storage forms (retinyl esters) and active forms (RA) from the addition of exogenous retinol (ROH), and these cells were very responsive to the growth inhibitory effects of ROH. MCF-7 cells produced small amounts of RA and responded moderately to the growth inhibitory effects of ROH. ER−, MDA MB-231 cells did not produce RA and were not responsive to the growth inhibiting effects of ROH.; In our third study we looked at whether treatment with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) would make a difference in ROH metabolism or growth responsiveness in the three cell lines. We found that at the concentrations used in our study (1μM) 4-HPR, the normal HMECs were the only cell line affected by 4-HPR treatment. HMECs exhibited greater cellular uptake of ROH, as well as a sequestering of cellular ROH. In addition they produced more RA and were growth inhibited to a greater extent when treated with 4-HPR and ROH. We conclude that carcinogenic mammary cells have altered metabolism and growth responsiveness to ROH such that this may contribute to carcinogenesis.