title: P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis.
abstract: Clinical studies show that estrogen receptor-α (ER) expressing tumors tend to have better prognosis, respond to antiestrogen therapy and have wild-type p53. Conversely, tumors with inactivating mutations in p53 tend to have worse outcomes and to be ER-negative and unresponsive to antihormone treatment. Previous studies from our laboratory have shown that p53 regulates ER expression transcriptionally, by binding the ER promoter and forming a complex with CARM1, CBP, c-Jun, RNA polymerase II and Sp1. In this study, the MMTV-Wnt-1 transgenic mouse model was used to demonstrate that p53 regulation of ER expression and function is not solely an in vitro phenomenon, but it is also operational in mammary tumorigenesis in vivo. The expression of ER and the ability to respond to tamoxifen were determined in mammary tumors arising in p53 wild type (WT) or p53 heterozygous (HT) animals carrying the Wnt-1 transgene. In p53 WT mice, development of ER-positive tumors was delayed by tamoxifen treatment, while tumors arising in p53 HT mice had significantly reduced levels of ER and were not affected by tamoxifen. P53 null tumors were also found in the p53 HT mice and these tumors were ER-negative. ER expression was upregulated in mouse mammary tumor cell lines following transfection with WT p53 or treatment with doxorubicin. These data demonstrate that p53 regulates ER expression in vivo, and affects response to tamoxifen. Results also provide an explanation for the concordant relationship between these prognostic proteins in human breast tumors.
authors.affiliation: Department of Molecular Carcinogenesis, The Virginia Harris Cockrell Cancer Research Center at The University of Texas MD Anderson Cancer Center, Science Park Research Division, 1808 Park Road 1C, Smithville, TX 78957, USA. rfyoung@mdanderson.org
authors.forename: Robin
authors.initials: R
authors.lastname: Fuchs-Young
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Shirley
authors.forename: Isabel
authors.initials: I
authors.lastname: Lambertz
authors.forename: Jennifer K L
authors.initials: JK
authors.lastname: Colby
authors.forename: Jie
authors.initials: J
authors.lastname: Tian
authors.forename: Dennis
authors.initials: D
authors.lastname: Johnston
authors.forename: Irma B
authors.initials: IB
authors.lastname: Gimenez-Conti
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Conti
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006579:Heterozygote; D019656:Loss of Heterozygosity; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013629:Tamoxifen / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D016159:Tumor Suppressor Protein p53; D051155:Wnt1 Protein; D013629:Tamoxifen