Suppression of pRB expression in normal human mammary epithelial cells is associated with resistance to all-trans-retinoic acid but not N-(4-hydroxylphenyl)-retinamide.
Despite the widespread clinical use of synthetic and naturally occurring retinoids, the down stream targets of retinoids have not been fully characterized. We observe that G(1/0)-phase arrest induced by all-trans-retinoic acid (ATRA) in normal human mammary epithelial cells (HMECs) is temporally associated with a significant decrease in the levels of hyperphosphorylated retinoblastoma protein (pRB). Suppression of pRB protein expression in HMECs by retroviral-mediated expression of the E7 protein of the human papillomavirus strain 16 (HPV-16) was associated with resistance to ATRA-mediated growth arrest but not to the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR or fenretinide). 4-HPR but not ATRA induced apoptosis in HMECs independent of the level of pRB protein expression. These observations suggest that ATRA- but not 4-HPR-mediated growth arrest may be dependent on the coordinated expression of pRB and emphasize the chemotherapeutic potential of 4-HPR, particularly for suppressing growth of tumors lacking pRB function.
Dietze
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Division of Medical Oncology, Duke University Medical Center, Durhlam, NC 27710, USA.
Yee
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Seewaldt
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001940:Breast / Q000166:cytology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D017313:Fenretinide; D014212:Tretinoin