Dysregulated expression of cyclin D1 in normal human mammary epithelial cells inhibits all-trans-retinoic acid-mediated G(0)/G(1)-Phase arrest and differentiation in vitro

Overexpression of cyclin D1 protein is observed in the majority of breast c ancers, suggesting that dysregulated expression of cyclin D1 might be a cri tical event in breast cancer carcinogenesis. We investigated whether retrov iral-mediated expression of cyclin D1 might affect all-trans-retinoic acid (ATRA)-mediated growth inhibition and differentiation of normal cultured hu man mammary epithelial cells (HMECs), HMECs treated with 1.0 mu M ATRA unde rgo irreversible growth inhibition starting at 24 h and complete G(0)/G(1)- phase arrest by Day 3. Cyclin D1 protein levels are observed to decrease in association with the initiation of growth arrest starting at 24 h and then increase by approximately 35% on Day 3, Concomitant with this observed inc rease in cyclin D1, HMECs undergo morphologic changes consistent with progr ession to a more differentiated phenotype, including an increase in cell si ze, increased cell spreading, increased tonofilaments, and accumulation of cytoplasmic vesicles containing lipid. Dysregulated expression of cyclin D1 in HMECs results in inhibition of G(0)/G(1)-phase arrest mediated by ATRA. In addition, HMECs expressing exogenous cyclin D1 are resistant to differe ntiation by ATRA. Our results suggest that coordinated expression of cyclin D1 may be critical for normal mammary epithelial cell homeostasis, and dys regulated expression of cyclin D1 might result in retinoid resistance and p romote mammary carcinogenesis, (C) 1999 Academic Press.