Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts.
In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.
D'Assoro
A B
AB
Department of Biochemistry and Molecular Biology, Tumor Biology Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Busby
R
R
Acu
I D
ID
Quatraro
C
C
Reinholz
M M
MM
Farrugia
D J
DJ
Schroeder
M A
MA
Allen
C
C
Stivala
F
F
Galanis
E
E
Salisbury
J L
JL
D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus; D018385:Centrosome / Q000648:ultrastructure*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010641:Phenotype; D008941:Spindle Apparatus; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D047628:Estrogen Receptor alpha; D016159:Tumor Suppressor Protein p53