The half maximal inhibitory concentrations (IC50) of tamoxifen in MCF-7 and LCC2 cell lines were 6.5 M and 67.7 M, respectively. and CD31 expression, and increased apoptotic cell death. Our findings identify CDK7 as a possible therapeutic target for breast cancer whether it is sensitive or resistant to tamoxifen therapy. levels. We found a positive correlation between and mRNA levels in TCGA breast cancer samples (Figure 1a) (rho = 0.41; = 0.02) and ER+ breast cancer samples (rho = 0.27; 0.001) (Figure 1b). High expression of (first sextile) was associated with significantly shorter overall survival (OS) HS-10296 hydrochloride for only ER+ breast cancer patients (= 0.01). Cox proportional hazards regression analysis of OS yielded a univariate hazard ratio (HR) of 2.64 (95% CI, 2.33C5.22; = 0.005) and a multivariate HR (adjusted for age and expression) of 2.7 (95% CI, 1.24C5.92; = 0.012) (Figure 1c). We next analyzed microarray data for a cohort of breast cancer patients receiving tamoxifen. The median OS duration was 68.5 months for patients with high expression and not reached for patients with low (Figure 1d). The Cox regression analysis of OS yielded an HR of 1 1.5 (95% CI, 1.15C1.96; = 0.0028). Because CDK7 is a master regulator oncogenes expression, such as MYC, we next explored the relationship between CDK7 and MYC expression. Our data revealed a significant correlation between and expression. We found a significant correlation (rho = 0.41; = 0.02) between CDK7 and expression in patients with ESR+ breast cancer treated with tamoxifen (Figure 1e). Furthermore, we found that median OS durations in patients with ER+ breast cancer receiving tamoxifen were longer when expression levels (where the cutoff point is 0.71) were lower (median OS, 79.8 months for high expression group and not reached for low expression group; HR, CDC42EP2 1.49; 95% CI, 1.07C2.08; = 0.0177) (Figure 1f). Finally, as shown in Figure 1g, we found that MYC expression correlates positively with ER1 expression in breast cancer patients receiving tamoxifen (rho = 0.46, 0.0001) Open in a separate window Figure 1 The relationship between cyclin dependent kinase (CDK7) expression and survival in breast cancer patients. Scatter plots of the HS-10296 hydrochloride Spearman rank-order correlation between (a) CDK7 and estrogen receptor alpha or 1 (ESR1) expression in 981 patients with breast cancer and (b) 715 patients with ER+ breast cancer. Data are from TCGA samples (RNASEqv2 data type). (c) KaplanCMeier curves comparing overall survival (OS) in patients with ER+ breast cancer stratified by CDK7 expression level. (d) KaplanCMeier curves comparing OS in patients with ER+ HS-10296 hydrochloride breast cancer receiving tamoxifen (TAM) by CDK7 expression level. (e) Scatter plot showing correlation between CDK7 and MYC expression in breast cancer patients receiving tamoxifen. (f) KaplanCMeier curves comparing OS in breast cancer patients receiving tamoxifen by HS-10296 hydrochloride MYC expression level. (g) Scatter plot showing the correlation between MYC and ESR1 expression in breast cancer patients receiving tamoxifen. 2.2. Targeting CDK7 Decreases Estrogen Receptor (ER) Activation The results of the TCGA analysis prompted us to examine the relationship between CDK7 and ER- expression in tamoxifen-sensitive and -resistant cell lines. HS-10296 hydrochloride To establish the in vitro working model, we screened the CDK7 expression level in the tamoxifen-sensitive MCF-7 cell line and its tamoxifen resistant counterpart LCC2 cells. We found that CDK7 expression levels in LCC2 cells were higher than those in MCF-7 cells (Figure 2a). Open in a separate window Figure 2 Expression of CDK7 in tamoxifen-sensitive and tamoxifen-resistant breast cancer cell lines. (a).
