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Phosphorylation of p90RSK Is Associated With Increased Response to Neoadjuvant Chemotherapy in ER-positive Breast Cancer

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Phosphorylation of p90RSK Is Associated With Increased Response to Neoadjuvant Chemotherapy in ER-positive Breast Cancer

Hyeong-Gon Moon et al. BMC Cancer.

Abstract

Background: The clinical implication of Ras/Raf/ERK pathway activity in breast cancer tissue and its association with response to chemotherapy is controversial. We aimed to explore the value of p90RSK phosphorylation, a downstram molecule of the pathway, in predicting chemotherapy response in breast cancer.

Methods: The expression of phosphorylated p90RSK (phospho-p90RSK) and chemotherapy response was measured in 11 breast cancer cell lines and 21 breast cancer tissues. The predictive value of phospho-p90RSK was validated in core needle biopsy specimens of 112 locally advanced breast cancer patients who received anthracycline and taxane-based neoadjuvant chemotherapy.

Results: In 11 breast cancer cell lines, the relative expression of phospho-p90RSK was inversely correlated with cell survival after doxorubicin treatment (p = 0.021). Similar association was observed in fresh tissues from 21 breast cancer patients in terms of clinical response. In paraffin-embedded, formalin-fixed tissues from core needle biopsy tissues from 112 patients, positive phospho-p90RSK expression was associated with greater tumor shrinkage and smaller post-chemotherapy tumor size. The association between phospho-p90RSK expression and chemotherapy response was more evident in estrogen receptor(ER)-positive tumors. The expression of phosphor-p90RSK did not show a significant relationship with the incidence of pCR. P90RSK silencing using siRNA did not affect the cancer cell's response to doxorubicin, and the expression of phospho-p90RSK was highly correlated with other Ras/Raf/ERK pathway activation.

Conclusion: Our results suggest that phospho-p90RSK expression, which reflects the tumor's Ras/Raf/ERK/p90RSK pathway activation can be a potential predictive marker for chemotherapy response in ER-positive breast cancer which needs further independent validation.

Figures

Figure 1
Figure 1
The expression of phospho-p90RSK in various breast cancer cell lines and doxorubicin sensitivity. The levels of protein expression of phospho-p90RSK and total p90RSK were examined in 11 breast cancer cell lines (a). The scattered plot for correlation analysis between relative phospho-p90RSK expression and sensitivity to doxorubicin is shown (b). Cell survival* denotes for the proportion of cancer cells surviving after doxorubicin 10uM treatment. The expression status of ER and HER2 in various breast cancer cell lines was determined by the works of **Subik et al. [14] and ***Neve et al. [15].
Figure 2
Figure 2
The expression of phospho-p90RSK in human breast cancer undergoing neoadjuvant chemotherapy. In 10 locally breast cancer patients, phospho-p90RSK and total p90RSK expression were measured by western blotting in core needle biopsy specimens of breast cancer before initiation of neoadjuvant chemotherapy. Patients were classified according to RECIST criteria determined by the treating physician (a and b). In 11 patients in whom the pre-chemotherapy and post-chemotherapy magnetic resonance imaging were available, the expression of phospho-p90RSK in tumor tissue and their corresponding radiologic tumor volume shrinkage are shown in (b).
Figure 3
Figure 3
Immunohistochemical staining against phospho-p90RSK in human breast cancer tissue. Protein expression of phospho-p90RSK in human breast cancer tissue was examined by immunohistochemistry. In upper panels, the representative immunohistochemical staining images of phospho-p90RSK negative (a), weak (b), and strong (c) expression are shown (magnification X10). In lower panels, X20 magnified images corresponding to the red-dashed square are shown.
Figure 4
Figure 4
Phospho-p90RSK expression and response to neoadjuvant chemotherapy. In 112 locally advanced breast cancer patients, the expression of phospho-p90RSK expression and the radiologic tumor size shrinkage were examined. Pre-chemotherapy radiologic tumor size and postchemotherapy tumor size (a), proportional tumor size reduction, and post-chemotherapy pathologic tumor size (b) were examined in all tumors (left panel), estrogen receptor-positive tumors (middle panel), and estrogen receptor-negative tumors (right panel). * denotes for p < 0.05 from Student’s t-test.
Figure 5
Figure 5
Results of p90RSK gene silencing in cancer cell lines and various Raf/Ras/ERK pathway activation in human breast cancer. p90RSK inhibition was done in MCF7 and ZR-75-1 cells by using siRNA against p90RSK. Student t-test showed no significant difference in cell proliferation in cells treated with siRNA against p90RSK and cells treated with scramble siRNA (a). The expression levels of total and phosphorylated various Raf/Ras/ERK pathway molecules were measured in primary breast cancer tissues from 20 breast cancer patients.

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