Molecular and Cellular Biochemistry

, Volume 379, Issue 1–2, pp 213–227 | Cite as

Restoration of wild-type p53 in drug-resistant mouse breast cancer cells leads to differential gene expression, but is not sufficient to overcome the malignant phenotype



We established a breast cancer cell line from a fast growing mouse WAP-SVT/t breast tumor. Cells from this line, SVTneg2, switched off T-antigen expression, carry a missense mutation at the p53 codon 242 (mouse G242 corresponds to human hot spot mutation G245), are malignantly transformed, highly aneuploid and very insensitive to apoptotic stimuli. To examine the influence of wild-type p53 (wtp53) restoration on the behavior of the SVTneg2 cells, we transfected these cells with wtp53 and generated three permanent cell lines expressing wtp53. Interestingly, restoration of p53 had no influence on chemotherapy sensitivity and the transformation capacity of these breast cancer cells, but markedly changed the gene expression of wtp53-dependent genes after doxorubicin treatment. We postulate that restoration of p53 leads to massive changes in gene expression and to a reduced proliferation rate, but is not sufficient to overcome the malignant phenotype and the chemoresistance of SVTneg2.


Trp53 p53 restoration Aneuploidy Chemoresistance Breast cancer 



We acknowledge Bianca Berg for technical assistance. We thank Roland Bell for editing the English version of this manuscript.

Supplementary material

11010_2013_1643_MOESM1_ESM.pptx (99 kb)
Supplementary Fig. 1 Gene expression profile of two differentially regulated genes. The figure shows examples of the expression profile of E2f1 and Cdk1 in the mammary gland epithelial cells of three normal mice, five SVT/t breast cancer and two breast cancer derived cell lines (SVTpos1 and SVTneg2). The expression values are shown in arbitrary units (AU). RNA was isolated from mammary gland tissue from three normal NMRI mice, five WAP-SVT/t breast cancers and two breast cancer derived cell lines (SVTpos1 and SVTneg2) in accordance with the manufacturer’s protocol (RNAzol PeQLab, Biotechnology GmbH). RNA was then hybridized to Affymetrix’s Mouse Expression Set 430A and scanned with the GeneChip Scanner 3000. Further analyses were performed with CorrXpression [79] (PPTX 99 kb)
11010_2013_1643_MOESM2_ESM.pptx (5.2 mb)
Supplementary Fig. 2 SA-β-gal staining under standard conditions for SVTneg2* (a) and SVTneg2·p53cl.7 (b) (magnification ×100), after 48 h treatment with 1 μM doxorubicin for SVTneg2* (c) and (e) (magnification ×40 and ×100) and for SVTneg2·p53cl.13 (d) and (f) (magnification ×40 and ×100); (g) SA-b-Gal positive cells for SVTneg2* and SVTneg2·p53 cells after 48 h doxorubicin incubation were quantified and expressed as % of total cell numbers. Error bars indicate the mean ± SD of three independent staining (PPTX 5281 kb)
11010_2013_1643_MOESM3_ESM.pptx (86 kb)
Supplementary Fig. 3 Wt-p53 restoration leads to a reduced proliferation rate, but is not sufficient to overcome chemoresistance. (A) Flow cytometry analysis of Annexin-V-FITC-labeled SVTneg2* and SVTneg2·p53 cells after 24, 48 and 72 h doxorubicin treatment. The graph shows the  % of Annexin-V positive cells. (B) BrdU proliferation assay. SVTneg2* and SVTneg2·p53 cells were incubated with and without doxorubicin and BrdU labeled. (C) Long term survival assessment by soft agar assays with or without the addition of 0.5 μM doxorubicin. The diagram exhibits the relative colony growth in ± doxorubicin treated cells. Error bars indicate the mean ± SD of three (BrdU and Flow cytometry) or two (Soft agar) independent experiments (PPTX 87 kb)
11010_2013_1643_MOESM4_ESM.pptx (235 kb)
Supplementary Fig. 4 Relative gene expression of Mdm2, Puma (Bbc3), Assp1 and Aspp2 under standard culture conditions and doxorubicin treatment. Mdm2 gene expression was almost comparable in all SVTneg2 cell lines with or without doxorubicin treatment. Puma gene expression remained unchanged after wtp53 restoration under standard culture conditions, but differed significantly under doxorubicin treatment. Gene expression of Aspp1 and Assp2 was affected by wtp53 restoration. Aspp1 and Assp2 expression increased slightly in SVTneg2·p53 cells under standard culture conditions and as well as for Aspp1 under doxorubicin treatment. However, under doxorubicin treatment, Aspp2 gene expression was markedly increased in SVTneg2·p53 cells and remained unchanged in SVTneg2* cells (PPTX 236 kb)
11010_2013_1643_MOESM5_ESM.pptx (202 kb)
Supplementary Fig. 5 Semiquantitative RT–PCR analysis. Total RNA was extracted and reverse transcribed into cDNA. Semiquantitative PCR was performed for Gapdh, p53, p21, Mdm2, Mdm4; p16/19, Cyclin G1 (Ccng1), Enigma (Pdlim7) and Hoxa5. Cell cycle numbers and the size of the expected PCR products are indicated. The complete primer list is presented in Supplementary Table 1 (PPTX 202 kb)
11010_2013_1643_MOESM6_ESM.docx (18 kb)
Supplementary Table 1 Primers were designed with the help of MacMolly Tetra and Primer-Blast. For Enigma, Mmd2 and Mdm4 primer sequences were taken from previous studies [23, 77, 78] (DOCX 19 kb)


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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Institute of BiochemistryCharité—Universitätsmedizin BerlinBerlinGermany

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