Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system

Mariam A. Stoff-Khalili, Alexander Stoff, Angel A. Rivera, Nilam S. Banerjee, Maaike Everts, Scott Young, Gene P. Siegal, Dirk F. Richter, Minghui Wang, Peter Dall, J. Michael Mathis, Zeng B. Zhu, David T. Curiel

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin.

METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver.

RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells.

CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast.

Original languageEnglish
Pages (from-to)R1141-R1152
JournalBreast cancer research : BCR
Volume7
Issue number6
DOIs
StatePublished - 1 Jan 2005

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Breast Neoplasms
Liver Neoplasms
Luciferases
Adenoviridae
Cell Line
Genetic Therapy
Secretory Leukocyte Peptidase Inhibitor
Chemokine CXCL12
CXC Chemokines
Tropism
Neoplasm Genes
Liver
Cyclooxygenase 2
Transgenes
Reporter Genes
Transcriptome
Human Activities
Glycoproteins
Therapeutics
Fibroblasts

Cite this

Stoff-Khalili, M. A., Stoff, A., Rivera, A. A., Banerjee, N. S., Everts, M., Young, S., ... Curiel, D. T. (2005). Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system. Breast cancer research : BCR, 7(6), R1141-R1152. https://doi.org/10.1186/bcr1353
Stoff-Khalili, Mariam A. ; Stoff, Alexander ; Rivera, Angel A. ; Banerjee, Nilam S. ; Everts, Maaike ; Young, Scott ; Siegal, Gene P. ; Richter, Dirk F. ; Wang, Minghui ; Dall, Peter ; Mathis, J. Michael ; Zhu, Zeng B. ; Curiel, David T. / Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system. In: Breast cancer research : BCR. 2005 ; Vol. 7, No. 6. pp. R1141-R1152.
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abstract = "INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin.METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver.RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells.CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast.",
author = "Stoff-Khalili, {Mariam A.} and Alexander Stoff and Rivera, {Angel A.} and Banerjee, {Nilam S.} and Maaike Everts and Scott Young and Siegal, {Gene P.} and Richter, {Dirk F.} and Minghui Wang and Peter Dall and Mathis, {J. Michael} and Zhu, {Zeng B.} and Curiel, {David T.}",
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Stoff-Khalili, MA, Stoff, A, Rivera, AA, Banerjee, NS, Everts, M, Young, S, Siegal, GP, Richter, DF, Wang, M, Dall, P, Mathis, JM, Zhu, ZB & Curiel, DT 2005, 'Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system', Breast cancer research : BCR, vol. 7, no. 6, pp. R1141-R1152. https://doi.org/10.1186/bcr1353

Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system. / Stoff-Khalili, Mariam A.; Stoff, Alexander; Rivera, Angel A.; Banerjee, Nilam S.; Everts, Maaike; Young, Scott; Siegal, Gene P.; Richter, Dirk F.; Wang, Minghui; Dall, Peter; Mathis, J. Michael; Zhu, Zeng B.; Curiel, David T.

In: Breast cancer research : BCR, Vol. 7, No. 6, 01.01.2005, p. R1141-R1152.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Preclinical evaluation of transcriptional targeting strategies for carcinoma of the breast in a tissue slice model system

AU - Stoff-Khalili, Mariam A.

AU - Stoff, Alexander

AU - Rivera, Angel A.

AU - Banerjee, Nilam S.

AU - Everts, Maaike

AU - Young, Scott

AU - Siegal, Gene P.

AU - Richter, Dirk F.

AU - Wang, Minghui

AU - Dall, Peter

AU - Mathis, J. Michael

AU - Zhu, Zeng B.

AU - Curiel, David T.

PY - 2005/1/1

Y1 - 2005/1/1

N2 - INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin.METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver.RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells.CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast.

AB - INTRODUCTION: In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Adenoviral vector mediated strategies for breast cancer gene therapy and virotherapy are a promising novel therapeutic platform for the treatment of breast cancer. However, the promiscuous tropism of adenoviruses (Ads) is a major concern. Employing tissue specific promoters (TSPs) to restrict transgene expression or viral replication is an effective way to increase specificity towards tumor tissues and to reduce adverse effects in non-target tissues such as the liver. In this regard, candidate breast cancer TSPs include promoters of the genes for the epithelial glycoprotein 2 (EGP-2), cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (stromal-cell-derived factor, CXCR4), secretory leukoprotease inhibitor (SLPI) and survivin.METHODS: We employed E1-deleted Ads that express the reporter gene luciferase under the control of the promoters of interest. We evaluated this class of vectors in various established breast cancer cell lines, primary breast cancer cells and finally in the most stringent preclinical available substrate system, constituted by precision cut tissue slices of human breast cancer and liver.RESULTS: Overall, the CXCR4 promoter exhibited the highest luciferase activity in breast cancer cell lines, primary breast cancer cells and breast cancer tissue slices. Importantly, the CXCR4 promoter displayed a very low activity in human primary fibroblasts and human liver tissue slices. Interestingly, gene expression profiles correlated with the promoter activities both in breast cancer cell lines and primary breast cancer cells.CONCLUSION: These data suggest that the CXCR4 promoter has an ideal 'breast cancer-on/liver-off' profile, and could, therefore, be a powerful tool in Ad vector based gene therapy or virotherapy of the carcinoma of the breast.

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U2 - 10.1186/bcr1353

DO - 10.1186/bcr1353

M3 - Article

C2 - 16457694

AN - SCOPUS:34447636732

VL - 7

SP - R1141-R1152

JO - Breast cancer research : BCR

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