PSMD9 expression predicts radiotherapy response in breast cancer

Fiona E. Langlands, David Dodwell, Andrew M. Hanby, Kieran Horgan, Rebecca A. Millican-Slater, Valerie Speirs, Eldo T. Verghese, Laura Smith, Thomas A. Hughes

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Abstract

BACKGROUND: More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.

METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.

RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.

CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

Original languageEnglish
Article number73
Number of pages8
JournalMolecular Cancer
Volume13
DOIs
Publication statusPublished - 28 Mar 2014

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Radio
Radiotherapy
Breast Neoplasms
Neoplasms
Proteasome Inhibitors
Recurrence
Cell Line
Small Interfering RNA
Intrinsic Factor
Adjuvant Radiotherapy
Proteasome Endopeptidase Complex
Immunohistochemistry
Odds Ratio
Regression Analysis
Incidence
Therapeutics
Pharmaceutical Preparations
ATP dependent 26S protease

Keywords

  • predictive marker
  • radiotherapy
  • proteasome

Cite this

Langlands, F. E., Dodwell, D., Hanby, A. M., Horgan, K., Millican-Slater, R. A., Speirs, V., ... Hughes, T. A. (2014). PSMD9 expression predicts radiotherapy response in breast cancer. Molecular Cancer, 13, [73]. https://doi.org/10.1186/1476-4598-13-73

PSMD9 expression predicts radiotherapy response in breast cancer. / Langlands, Fiona E.; Dodwell, David; Hanby, Andrew M.; Horgan, Kieran; Millican-Slater, Rebecca A.; Speirs, Valerie; Verghese, Eldo T.; Smith, Laura; Hughes, Thomas A.

In: Molecular Cancer, Vol. 13, 73, 28.03.2014.

Research output: Contribution to journalArticle

Langlands, FE, Dodwell, D, Hanby, AM, Horgan, K, Millican-Slater, RA, Speirs, V, Verghese, ET, Smith, L & Hughes, TA 2014, 'PSMD9 expression predicts radiotherapy response in breast cancer', Molecular Cancer, vol. 13, 73. https://doi.org/10.1186/1476-4598-13-73
Langlands FE, Dodwell D, Hanby AM, Horgan K, Millican-Slater RA, Speirs V et al. PSMD9 expression predicts radiotherapy response in breast cancer. Molecular Cancer. 2014 Mar 28;13. 73. https://doi.org/10.1186/1476-4598-13-73
Langlands, Fiona E. ; Dodwell, David ; Hanby, Andrew M. ; Horgan, Kieran ; Millican-Slater, Rebecca A. ; Speirs, Valerie ; Verghese, Eldo T. ; Smith, Laura ; Hughes, Thomas A. / PSMD9 expression predicts radiotherapy response in breast cancer. In: Molecular Cancer. 2014 ; Vol. 13.
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abstract = "BACKGROUND: More than 50{\%} of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4{\%}) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.",
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note = "This work was supported by the Breast Cancer Campaign (FEL, LS, VS, TAH), the Breast Cancer Research Action Group (TAH), and the Medical Research Council (ETV). The funders had no roles in designing or carrying out the research, or in preparing the manuscript.",
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T1 - PSMD9 expression predicts radiotherapy response in breast cancer

AU - Langlands, Fiona E.

AU - Dodwell, David

AU - Hanby, Andrew M.

AU - Horgan, Kieran

AU - Millican-Slater, Rebecca A.

AU - Speirs, Valerie

AU - Verghese, Eldo T.

AU - Smith, Laura

AU - Hughes, Thomas A.

N1 - This work was supported by the Breast Cancer Campaign (FEL, LS, VS, TAH), the Breast Cancer Research Action Group (TAH), and the Medical Research Council (ETV). The funders had no roles in designing or carrying out the research, or in preparing the manuscript.

PY - 2014/3/28

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N2 - BACKGROUND: More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

AB - BACKGROUND: More than 50% of cancer patients are recommended to receive radiotherapy. Recommendations are based mainly on clinical and pathological factors and not intrinsic tumour radio-sensitivity. Use of radiotherapy according to predictive markers would potentially reduce costly over-treatment, and improve the treatment risk-benefit ratio and cancer outcomes. Tumour expression of the 26S proteasome has been reported to predict radiotherapy response: low expression was associated with higher rates of local recurrence after radiotherapy, suggesting that low proteasome expression and activity was associated with radio-resistance. However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers. Our aim was to further analyse the relevance of 26S proteasome expression, focussing specifically on the PSMD9 subunit, in the largest clinical cohort to date, and to investigate the functional role of PSMD9 in radio-sensitivity in breast cancer cell lines.METHODS: We examined expression of PSMD9 using immunohistochemistry in a cohort of 157 breast cancer patients, including 32 cases (20.4%) that subsequently developed local recurrences. The value of expression as a prognostic or radiotherapy predictive marker was tested using Kaplan-Meier and Cox regression analyses. PSMD9 function was examined in breast cancer cell lines MCF7 and MDA-MB-231 using siRNA knock-downs and colony forming assays after irradiation.RESULTS: Low tumour PSMD9 expression was significantly associated with a reduced incidence of local recurrence in patients receiving adjuvant radiotherapy (univariate log rank p = 0.02; multivariate regression p = 0.009), but not in those treated without radiotherapy, suggesting that low PSMD9 expression was associated with relative tumour radio-sensitivity. In support of this, reduction of PSMD9 expression using siRNA in breast cancer cell lines in vitro sensitized cells to radiotherapy.CONCLUSIONS: We conclude that PSMD9 expression may predict radiotherapy benefit, with low expression indicative of relative radio-sensitivity, the opposite of previous reports relating to 26S proteasome expression. Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

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KW - proteasome

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