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Retinoic Acid-mediated G₁-S-Phase Arrest of Normal Human Mammary Epithelial Cells Is Independent of the Level of p53 Protein Expression¹

Division of Oncology, Department of Medicine [V. L. S.], Department of Medicinal Chemistry [E. C. D.], Division of Hospital Dentistry, Department of Restorative Dentistry [B. S. J.], and Division of General Internal Medicine, University of Washington, Department of Medicine [M. B. P.], University of Washington, and Division of Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington 98195 [S. J. C.]

Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of breast cancer. Despite the widespread clinical use of retinoids, specific target genes that are regulated by retinoids are relatively poorly characterized. We reported previously that all-trans-retinoic acid (ATRA) mediates G₁-S-phase arrest in normal human mammary epithelial cells (HMECs). The tumor suppressor gene p53 is thought to be a critical regulator of G₁-S-phase arrest mediated by DNA-damaging agents such as chemotherapy and radiation. The role of p53 protein expression in G₁-S-phase arrest mediated by the differentiating agent ATRA is unknown. Increased expression of p53 protein is observed in ATRA-treated HMECs at 72 h; however, initiation of G₁-S-phase arrest starts at 24 h, suggesting that this observed induction of p53 is a secondary event. Using retroviral-mediated gene transfer, we expressed the E6 protein of the human papillomavirus strain 16 (HPV-16) in HMECs. The HPV-16 E6 protein binds to p53 and targets it for degradation. Western analysis confirmed that HPV-16 E6-transduced HMECs had markedly decreased levels of p53 protein expression. Suppression of cellular p53 levels in HMECs did not alter the sensitivity of HMECs to ATRA-mediated growth arrest. Our studies suggest that ATRA-mediated G₁-S-phase arrest is independent of the level of p53 protein expression. We also tested the ability of estrogen and antiestrogens to induce growth arrest in HMECs lacking p53 expression and found no decrease in the sensitivity of these cells to these agents. Our results emphasize the chemotherapeutic potential of ATRA and antiestrogens, particularly for suppressing the growth of tumors lacking functional p53.

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