Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

D’Assoro, Antonino B.; Busby, Robert C.; Acu, Ilie D.; Quatraro, Cosima; Reinholz, Monica M.; Farrugia, Daniel J.; Schroeder, Mark A.; Allen, Cory; Stivala, Franca; Galanis, Evanthia; Salisbury, Jeffrey L.

doi:10.1038/onc.2008.18

Cited by 26 publications

(35 citation statements)

References 44 publications

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“…3B). The majority of these transcriptome and phenotypic changes arise independent of chromosomal instability, since we have previously demonstrated that cultured vMCF-7 DNP53 show a normal centrosome and mitotic spindle phenotypes, and that centrosome amplification and aberrant mitoses develop in vitro only following genotoxic stress or in the context of in vivo tumor growth (12).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously demonstrated that vMCF-7 DNP53 xenografts develop high-grade breast tumors characterized by phenotypic heterogeneity for the estrogen receptor · (ER·) and spontaneous metastatic spreading to the lung (12). Affimetrix microarray expression analysis revealed that 392 genes were uniquely expressed in vMCF-7 DNP53 1GX as compared to cultured vMCF-7 DNP53 cells, suggesting that in vivo tumor growth leads to additional transcriptome changes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The human breast cancer cell line MCF-7 (ATCC, Manassas, VA, USA), was modified to express a recombinant temperature sensitive p53 construct mutated at residue 135 to valine (vMCF-7 DNp53 ) as described previously (7,12,22). Cultures were maintained in EMEM medium containing 5 mM glutamine, 1% penicillin/ streptomycin, 20 μg/ml insulin and 10% FBS at 37˚C in 5% CO 2 , and the engineered clones were maintained under 500 μg/ml G418 selection.…”

Section: Methodsmentioning

confidence: 99%

“…In a p53-null mouse model for mammary tumorigenesis, impaired p53 function accelerates the development of CIN and tumor cell heterogeneity characterized by the loss of ER expression (20). Similarly, impaired p53 function leads to centrosome amplification, aberrant mitoses, development of high-grade breast tumors, ER tumor cell heterogeneity and distant metastases in an ER positive human breast cancer xenograft model (12). Recent studies have also implicated a novel role for p53 in the inhibition of tumor progression through suppression of CD44 expression and epithelial to mesenchymal transition (EMT) responsible for tumor self-renewal and metastasis (21).…”

Section: Introductionmentioning

confidence: 99%

“…This notwithstanding, breast tumors are thought to become refractory to conventional anti-cancer therapies due in part to tumor cell heterogeneity, which confers manifold options for resistance to a given treatment modality (9)(10)(11). The tumor suppressor p53, whose function is lost in 50% of human cancers, plays a key role in the maintenance of chromosomal stability through tight coordination of DNA replication with centrosome duplication, activation of cell cycle checkpoints following genotoxic stress, and initiation of programmed cell death if damaged DNA can not be repaired properly (5,7,12,13). P53 operates as a tumor suppressor mainly as a transcription factor that directly binds to the promoter region of target genes and activates or suppresses their transcription (14).…”

Section: Introductionmentioning

confidence: 99%

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Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts

et al. 2010

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Abstract. Development of chromosomal instability (CIN) and consequent phenotypic heterogeneity represent common events during breast cancer progression. Breast carcinomas harboring extensive chromosomal aberrations display a more aggressive behavior characterized by chemoresistance and the propensity to give rise to distant metastases. The tumor suppressor p53 plays a key role in the maintenance of chromosomal stability and tissue homeostasis through activation of cell cycle checkpoints following DNA damage and control of centrosome duplication that ensures equal chromosome segregation during cell division. Furthermore, p53 suppresses CD44 expression and the acquisition of stem cell-like properties responsible for epithelial to mesenchymal transition (EMT) and metastasis. In this study we employed MCF-7 breast cancer cells with endogenous wild-type p53, an engineered ) overexpressing a dominant negative p53val135 mutant, and cells re-cultured from vMCF-7 DNP53 tumor xenografts. We carried out an integrative transcriptome and cytogenetic analysis to characterize the mechanistic linkage between loss of p53 function, EMT and consequent establishment of invasive gene signatures during breast cancer progression. We demonstrate that abrogation of p53 function drives the early transcriptome changes responsible for cell proliferation, EMT and survival, while further transcriptome changes that occur during in vivo tumor progression are mechanistically linked to the development of CIN leading to a more invasive and metastatic breast cancer phenotype. Here we identified distinct novel non-canonical transcriptome networks involved in cell proliferation, EMT, chemoresistance and invasion that arise following abrogation of p53 function in vitro and development of CIN in vivo. These studies also have important translational implications since some of the nodal genes identified here are 'druggable' making them appropriate molecular targets for the treatment of breast carcinomas displaying mutant p53, EMT, CIN and high metastatic potential. IntroductionHuman breast tumors displaying an aggressive behavior are generally characterized by high tumor cell heterogeneity, which has been associated with the development of chromosomal instability (CIN) during tumor progression (1,2). Chromosomal instability represents a hallmark of solid tumors and is characterized by the high frequency of qualitative and quantitative chromosome abnormalities that arise during tumor progression (3). Centrosome duplication plays a critical role in the control of chromosomal stability through the establishment of bipolar mitotic spindles and propagation of a diploid karyotype (4,5). In normal cells, centrosome duplication is coordinated with DNA replication, ensuring the establishment of bipolar mitotic spindle leading to equal chromosome segregation (6-8). Although chromosomal instability may be present during the early stages of neoplastic transformation, the persistence of CIN during tumor progression and its causative role in the development of dista...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%