title: All-trans-retinoic acid mediates G1 arrest but not apoptosis of normal human mammary epithelial cells.
abstract: Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of certain malignancies. Loss of retinoic acid (RA) receptor-beta function may be an important event in mammary carcinogenesis, because the majority of breast cancers, in contrast to normal mammary epithelial cells, fail to express this receptor. We previously reported that all-trans-RA mediates G1 arrest as well as apoptosis in certain RAR beta-transduced breast cancer cell lines. We now report the effect of RA on normal human mammary epithelial cells (HMECs), which express functionally active retinoid receptors. We observe that RA induces growth suppression and G1 arrest of these HMECs but find no evidence that RA mediates apoptosis in these normal cell strains. This RA-induced G1 arrest is temporally associated with decreased levels of hyperphosphorylated retinoblastoma protein without any significant changes in c-myc, p53, p21, or p27 expression. Expression of cyclin D1, cyclin-dependent kinase 4, and cyclin E proteins, however, decreased in association with RA-mediated G1 arrest. Our studies suggest that growth inhibition, rather than apoptosis, may be a mechanism by which RA and RA receptors act to prevent the malignant transformation of normal mammary epithelial cells. The molecular target(s) of the activated RA receptors that mediate this G1 arrest in HMECs appear to be associated with a retinoblastoma-dependent pathway.
authors.affiliation: Department of Medicine, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: V L
authors.initials: VL
authors.lastname: Seewaldt
authors.forename: J H
authors.initials: JH
authors.lastname: Kim
authors.forename: L E
authors.initials: LE
authors.lastname: Caldwell
authors.forename: B S
authors.initials: BS
authors.lastname: Johnson
authors.forename: K
authors.initials: K
authors.lastname: Swisshelm
authors.forename: S J
authors.initials: SJ
authors.lastname: Collins
mesh_terms: D017209:Apoptosis; D015152:Blotting, Northern; D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D018168:Receptors, Retinoic Acid / Q000235:genetics; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016213:Cyclins; D006131:Growth Inhibitors; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D014212:Tretinoin; D004247:DNA; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases