Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo.

Pierfrancesco Tassone, Maria Teresa Di Martino, Monica Ventura, Antonella Pietragalla, Iole Cucinotto, Teresa Calimeri, Alessandra Bulotta, Paola Neri, Michele Caraglia, Pierosandro Tagliaferri

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Previous reports suggested a central role of BRCA1 in DNA-damage repair mechanisms elicited by cell exposure to anti-tumor agents. Here we studied if BRCA1-defective HCC1937 or BRCA1-reconstituted HCC1937/(WT)BRCA1 human breast cancer xenografts (HBCXs) generated in SCID mice were differentially sensitive to cisplatin (CDDP) in vivo and we investigated potential molecular correlates of this effect. RESULTS: CDDP induced almost complete growth inhibition of BRCA1-defective HBCXs, while BRCA1-reconstituted HBCXs were only partially inhibited. Cell cycle analysis showed a significant S- and G(2)/M blockade in BRCA1-defective as compared with parental BRCA1-reconstituted cells. Comparative gene expression profiling of HCC1937 and HCC1937/(WT)BRCA1 showed upregulation of RAD52 and XRCC4, whereas ERCC1 and RRM1 were downregulated. Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that BRCA1 is mostly involved in G(2)/M but also in G(1)/S-phase checkpoints as well as in several important signaling pathways, including IGF, VEGF, estrogen receptor, PI3K/AKT and EGF. METHODS: HCC1937 or HCC1937/(WT)BRCA1 HBCXs were generated in SCID mice. Animals were then weekly treated with 5 mg/kg CDDP i.p. or with vehicle for 4 w. Tumor volume and mice survival were evaluated. Tumors were retrieved from animals 12 hours after the last treatment with CDDP or vehicle treatment and the cell suspension underwent cell cycle analysis. Differential gene expression and pathway modulation between HCC1937 and HCC1937/(WT)BRCA1 cells were also studied. CONCLUSION: Our data suggest that BRCA1-defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum-derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer.

Original languageEnglish
Pages (from-to)648-653
Number of pages6
JournalCancer Biology and Therapy
Volume8
Issue number7
Publication statusPublished - Apr 2009

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Heterografts
Cisplatin
Breast Neoplasms
SCID Mice
Cell Cycle
S Phase Cell Cycle Checkpoints
Platinum Compounds
Vascular Endothelial Growth Factor Receptor
Gene Expression Profiling
Tumor Burden
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor
DNA Repair
Estrogen Receptors
DNA Damage
Neoplasms
Suspensions
Up-Regulation
Down-Regulation
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

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Tassone, P., Di Martino, M. T., Ventura, M., Pietragalla, A., Cucinotto, I., Calimeri, T., ... Tagliaferri, P. (2009). Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biology and Therapy, 8(7), 648-653.

Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. / Tassone, Pierfrancesco; Di Martino, Maria Teresa; Ventura, Monica; Pietragalla, Antonella; Cucinotto, Iole; Calimeri, Teresa; Bulotta, Alessandra; Neri, Paola; Caraglia, Michele; Tagliaferri, Pierosandro.

In: Cancer Biology and Therapy, Vol. 8, No. 7, 04.2009, p. 648-653.

Research output: Contribution to journalArticle

Tassone, P, Di Martino, MT, Ventura, M, Pietragalla, A, Cucinotto, I, Calimeri, T, Bulotta, A, Neri, P, Caraglia, M & Tagliaferri, P 2009, 'Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo.', Cancer Biology and Therapy, vol. 8, no. 7, pp. 648-653.
Tassone P, Di Martino MT, Ventura M, Pietragalla A, Cucinotto I, Calimeri T et al. Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. Cancer Biology and Therapy. 2009 Apr;8(7):648-653.
Tassone, Pierfrancesco ; Di Martino, Maria Teresa ; Ventura, Monica ; Pietragalla, Antonella ; Cucinotto, Iole ; Calimeri, Teresa ; Bulotta, Alessandra ; Neri, Paola ; Caraglia, Michele ; Tagliaferri, Pierosandro. / Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo. In: Cancer Biology and Therapy. 2009 ; Vol. 8, No. 7. pp. 648-653.
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abstract = "BACKGROUND: Previous reports suggested a central role of BRCA1 in DNA-damage repair mechanisms elicited by cell exposure to anti-tumor agents. Here we studied if BRCA1-defective HCC1937 or BRCA1-reconstituted HCC1937/(WT)BRCA1 human breast cancer xenografts (HBCXs) generated in SCID mice were differentially sensitive to cisplatin (CDDP) in vivo and we investigated potential molecular correlates of this effect. RESULTS: CDDP induced almost complete growth inhibition of BRCA1-defective HBCXs, while BRCA1-reconstituted HBCXs were only partially inhibited. Cell cycle analysis showed a significant S- and G(2)/M blockade in BRCA1-defective as compared with parental BRCA1-reconstituted cells. Comparative gene expression profiling of HCC1937 and HCC1937/(WT)BRCA1 showed upregulation of RAD52 and XRCC4, whereas ERCC1 and RRM1 were downregulated. Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that BRCA1 is mostly involved in G(2)/M but also in G(1)/S-phase checkpoints as well as in several important signaling pathways, including IGF, VEGF, estrogen receptor, PI3K/AKT and EGF. METHODS: HCC1937 or HCC1937/(WT)BRCA1 HBCXs were generated in SCID mice. Animals were then weekly treated with 5 mg/kg CDDP i.p. or with vehicle for 4 w. Tumor volume and mice survival were evaluated. Tumors were retrieved from animals 12 hours after the last treatment with CDDP or vehicle treatment and the cell suspension underwent cell cycle analysis. Differential gene expression and pathway modulation between HCC1937 and HCC1937/(WT)BRCA1 cells were also studied. CONCLUSION: Our data suggest that BRCA1-defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum-derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer.",
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T1 - Loss of BRCA1 function increases the antitumor activity of cisplatin against human breast cancer xenografts in vivo.

AU - Tassone, Pierfrancesco

AU - Di Martino, Maria Teresa

AU - Ventura, Monica

AU - Pietragalla, Antonella

AU - Cucinotto, Iole

AU - Calimeri, Teresa

AU - Bulotta, Alessandra

AU - Neri, Paola

AU - Caraglia, Michele

AU - Tagliaferri, Pierosandro

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N2 - BACKGROUND: Previous reports suggested a central role of BRCA1 in DNA-damage repair mechanisms elicited by cell exposure to anti-tumor agents. Here we studied if BRCA1-defective HCC1937 or BRCA1-reconstituted HCC1937/(WT)BRCA1 human breast cancer xenografts (HBCXs) generated in SCID mice were differentially sensitive to cisplatin (CDDP) in vivo and we investigated potential molecular correlates of this effect. RESULTS: CDDP induced almost complete growth inhibition of BRCA1-defective HBCXs, while BRCA1-reconstituted HBCXs were only partially inhibited. Cell cycle analysis showed a significant S- and G(2)/M blockade in BRCA1-defective as compared with parental BRCA1-reconstituted cells. Comparative gene expression profiling of HCC1937 and HCC1937/(WT)BRCA1 showed upregulation of RAD52 and XRCC4, whereas ERCC1 and RRM1 were downregulated. Pathway finder analysis of gene arrays data indicated perturbations of major proliferation and survival pathways suggesting that BRCA1 is mostly involved in G(2)/M but also in G(1)/S-phase checkpoints as well as in several important signaling pathways, including IGF, VEGF, estrogen receptor, PI3K/AKT and EGF. METHODS: HCC1937 or HCC1937/(WT)BRCA1 HBCXs were generated in SCID mice. Animals were then weekly treated with 5 mg/kg CDDP i.p. or with vehicle for 4 w. Tumor volume and mice survival were evaluated. Tumors were retrieved from animals 12 hours after the last treatment with CDDP or vehicle treatment and the cell suspension underwent cell cycle analysis. Differential gene expression and pathway modulation between HCC1937 and HCC1937/(WT)BRCA1 cells were also studied. CONCLUSION: Our data suggest that BRCA1-defective in vivo HBCXs express a molecular scenario predictive of high sensitivity to platinum-derived compounds strongly supporting the rationale for prospective tailored clinical trials in hereditary breast cancer.

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