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. 2011 Nov;130(2):399-408.
doi: 10.1007/s10549-010-1308-y. Epub 2010 Dec 30.

P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis

Robin Fuchs-Young  1 , Stephanie H Shirley, Isabel Lambertz, Jennifer K L Colby, Jie Tian, Dennis Johnston, Irma B Gimenez-Conti, Lawrence A Donehower, Claudio J Conti, Stephen D Hursting
Affiliations

P53 genotype as a determinant of ER expression and tamoxifen response in the MMTV-Wnt-1 model of mammary carcinogenesis

Robin Fuchs-Young et al. Breast Cancer Res Treat. 2011 Nov.

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.

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Conflict of interest statement

None of the authors have any conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves of MMTV-Wnt-1 transgenic mice with different p53 genotypes. Wnt-1 transgenic mice with WT p53 (n = 115) had a significantly longer tumor free interval (increased latency) compared to p53 HT mice (n = 83), P < 0.0001
Fig. 2
Fig. 2
Estrogen receptor expression in tumors arising in Wnt-1 transgenic animals varies with p53 genotype. a Southern analysis of tumors arising in Wnt-1 transgenics on a p53 HT background, showing tumors were either HT or null (LOH) for p53. Arrows denote bands from the p53 pseudogene (10 Kb), the p53 knockout (KO) allele (6.5 Kb), the p53 WT allele (~5 Kb) and effects of vehicle (HT Veh; n = 37), P = 0.67. b Estrogen receptor levels correlate with p53 status. ER mRNA levels were determined by QPCR, as described in the “Materials and methods” section. Compared to tumors from transgenic mice with WT p53, ER mRNA levels were reduced about 2-fold in tumors from p53 HT mice (* P = 0.03) and further reduced by 6-fold in tumors with LOH (HT with LOH) (* P = 0.004). Mammary tumors with LOH at the p53 locus had a 3-fold reduction in ER message levels compared to tumors arising in p53 HT mice that did not undergo LOH (** P < 0.001)
Fig. 3
Fig. 3
Immunolocalization of ERα in paraffin sections of mouse mammary tumors arising in MMTV-Wnt-1 transgenics. ER protein expression paralleled the level of ER message as determined by QPCR (Fig. 2). a Normal mammary gland adjacent to a p53 WT tumor (internal positive control), b p53 WT tumor, c p53 HT tumor, and d p53 null tumor
Fig. 4
Fig. 4
Increased expression of WT p53 in mammary tumor cells upregulates ER. a–c Mammary tumor cell lines 4T1, MMTV-Wnt-1 D4, and MMTV-Wnt-1 G4 were either mock transfected (no vector) or transiently transfected with 0.5 or 2.0 μg of WT p53 or a control, noncoding vector. Cell lines, G4 (d) and D4 (e), were treated with DNA-damaging agent doxorubicin (50 nM) for the time periods indicated in the figure. Results presented are representative Western blots of whole cell lysates and were sequentially probed with antibodies against ER, p53, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH, loading control) as described in the “Materials and methods” section
Fig. 5
Fig. 5
The effect of tamoxifen treatment on tumor development depends on p53 genotype. a Ten weeks of tamoxifen treatment significantly delayed tumorigenesis in Wnt-1 transgenics on a WT p53 background (WT Tam; n = 58) compared to vehicle (WT Veh; n = 57), P = 0.035. Conversely, tamoxifen treatment did not alter tumor development in Wnt-1 transgenics on a p53 HT background (HT Tam; n = 46) compared to vehicle (HT Veh; n = 37), P = 0.669. b Treatment with tamoxifen did not affect ER expression in tumors from Wnt-1 Tg mice with p53 WT (P = 0.41) or p53 HT (P = 0.38). Numbers at the base of each column refer to the number of tumors of each genotype/treatment group, which were analyzed by QPCR. Data are presented as ER mRNA expression relative to TBP (reference gene)
Fig. 6
Fig. 6
Hypothetical regulatory loop involving p53 and ER in the mammary gland. P53 up-regulates ER expression and ER upregulates p53 expression. While p53 leads to cell cycle arrest or apoptosis, activation of ER leads to proliferation, differentiation, and mammary gland development. This loop maintains a balance between proliferation and growth arrest in the mammary gland
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