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PSMD9 expression predicts radiotherapy response in breast cancer.

Langlands FE, Dodwell D, Hanby AM, Horgan K, Millican-Slater RA, Speirs V, Verghese ET, Smith L, Hughes TA - Mol. Cancer (2014)

Bottom Line: However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers.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.Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK. medlsmi@leeds.ac.uk.

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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Positive expression of PSMD9 is significantly associated with higher rates of local recurrences after RT in breast cancer. Kaplan–Meier analyses for local recurrence in patient groups with tumours showing positive (any appreciable; “pos”) or negative (no appreciable; “neg”) staining for PSMD9. A A mixed group of 157 patients. B Patients treated with RT. C Patients not treated with RT.
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Figure 3: Positive expression of PSMD9 is significantly associated with higher rates of local recurrences after RT in breast cancer. Kaplan–Meier analyses for local recurrence in patient groups with tumours showing positive (any appreciable; “pos”) or negative (no appreciable; “neg”) staining for PSMD9. A A mixed group of 157 patients. B Patients treated with RT. C Patients not treated with RT.

Mentions: PSMD9 expression was dichotomised in order to allow Kaplan-Meier analyses of the influence of PSMD9 on LR. Receiver operator curve analysis was performed in order to select a cut off objectively that gives the best balance between sensitivity and specificity for the end point of LR, and therefore allows the strongest use of these scoring data (Additional file 2: Figure S1). A cut off of 1 was selected, thereby defining tumours with no staining for PSMD9 as negative, and those with any staining as positive. Kaplan-Meier analyses were performed to study influences of PSMD9 expression on LR in the entire cohort (Figure 3A). Positive expression of PSMD9 was significantly associated with an increased LR rate (p = 0.03), suggesting that PSMD9 provides prognostic information. Moreover, when the cancer cohort was divided into patients treated with RT (n = 110) and patients treated without RT (n = 47) insights were gained into the predictive value of PSMD9 for RT (Figure 3B and C). It should be noted that type of surgical operation (wide local excision vs mastectomy) and lymph node status were the only significant clinico-pathological differences between the groups treated with or without RT (Additional file 3: Table S2); tumour size, grade or receptor expression did not differ significantly. Lymph node positivity and surgery type are used to select patients for RT, therefore these differences were expected. Positive expression of PSMD9 was significantly associated with LR specifically in patients who received RT (Figure 3B, p = 0.02), but not in those who did not receive RT (Figure 3C, p = 0.75).


PSMD9 expression predicts radiotherapy response in breast cancer.

Langlands FE, Dodwell D, Hanby AM, Horgan K, Millican-Slater RA, Speirs V, Verghese ET, Smith L, Hughes TA - Mol. Cancer (2014)

Positive expression of PSMD9 is significantly associated with higher rates of local recurrences after RT in breast cancer. Kaplan–Meier analyses for local recurrence in patient groups with tumours showing positive (any appreciable; “pos”) or negative (no appreciable; “neg”) staining for PSMD9. A A mixed group of 157 patients. B Patients treated with RT. C Patients not treated with RT.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230020&req=5

Figure 3: Positive expression of PSMD9 is significantly associated with higher rates of local recurrences after RT in breast cancer. Kaplan–Meier analyses for local recurrence in patient groups with tumours showing positive (any appreciable; “pos”) or negative (no appreciable; “neg”) staining for PSMD9. A A mixed group of 157 patients. B Patients treated with RT. C Patients not treated with RT.
Mentions: PSMD9 expression was dichotomised in order to allow Kaplan-Meier analyses of the influence of PSMD9 on LR. Receiver operator curve analysis was performed in order to select a cut off objectively that gives the best balance between sensitivity and specificity for the end point of LR, and therefore allows the strongest use of these scoring data (Additional file 2: Figure S1). A cut off of 1 was selected, thereby defining tumours with no staining for PSMD9 as negative, and those with any staining as positive. Kaplan-Meier analyses were performed to study influences of PSMD9 expression on LR in the entire cohort (Figure 3A). Positive expression of PSMD9 was significantly associated with an increased LR rate (p = 0.03), suggesting that PSMD9 provides prognostic information. Moreover, when the cancer cohort was divided into patients treated with RT (n = 110) and patients treated without RT (n = 47) insights were gained into the predictive value of PSMD9 for RT (Figure 3B and C). It should be noted that type of surgical operation (wide local excision vs mastectomy) and lymph node status were the only significant clinico-pathological differences between the groups treated with or without RT (Additional file 3: Table S2); tumour size, grade or receptor expression did not differ significantly. Lymph node positivity and surgery type are used to select patients for RT, therefore these differences were expected. Positive expression of PSMD9 was significantly associated with LR specifically in patients who received RT (Figure 3B, p = 0.02), but not in those who did not receive RT (Figure 3C, p = 0.75).

Bottom Line: However, this conclusion is at odds with the emerging use of proteasome inhibitors as radio-sensitizers.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.Our conclusion is compatible with use of proteasome inhibitors as radio-sensitizers, and highlights PSMD9 as a potential target for radio-sensitizing drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK. medlsmi@leeds.ac.uk.

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.

Show MeSH
Related in: MedlinePlus