Results: 5

1.
Figure 5

Figure 5. From: CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling.

Mechanism of CXCR4-dependent maintenance of prostate cancer progenitors in tamoxifen-resistant MCF7 cells. CXCL4 signalling induces the activation of AhR-dependent gene transcription contributing to expanded progenitor population and tumour growth. Targeting CXCR4 signalling with small molecule inhibitors may be beneficial in eliminating prostate cancer stem-like cells in tamoxifen-resistant tumours.

A Dubrovska, et al. Br J Cancer. 2012 June 26;107(1):43-52.
2.
Figure 1

Figure 1. From: CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling.

High expression level of ABCG2 in tamoxifen-resistant MCF7 cells line is associated with an increase in the cancer progenitor population. (A) MCF7(TAM-R) cells showed an increased level of ABCG2 expression as analysed by RT–PCR and western blot analysis. (B) Side population analysis and (C) Aldefluor assay showed a significant enrichment of the progenitor population within MCF7(TAM-R) cells compared with the tamoxifen-sensitive MCF7 cells (*P value<0.05).

A Dubrovska, et al. Br J Cancer. 2012 June 26;107(1):43-52.
3.
Figure 2

Figure 2. From: CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling.

MCF7(TAM-R) cells are more sensitive to modulation of CXCR4 signalling than MCF7 cells and tamoxifen-resistant progenitor cell population, and could be specifically inhibited by CXCR4 antagonist AMD3100. (A) AKT inhibitor IV (IC50=1.94 × 10−7) and CXCR4 antagonist AMD3100 (IC50=2.55 × 10−7) are potent inhibitors of SP in tamoxifen-resistant cell. MCF7(TAM-R) cells were cultured in tamoxifen-free growth medium in the presence of inhibitors at indicated concentration for 5 days. The culture medium was replenished daily. (B) The CXCR4 knockdown in MCF7(TAM-R) cells showed a decrease in the SP and growth inhibition compared with scrambled shRNA-transduced control MCF7(TAM-R) cells. (C) MCF7(TAM-R) cells are more sensitive to modulation of CXCR4 signalling than MCF7 cells. The cells were cultured in tamoxifen-free growth medium in the presence of inhibitors at indicated concentration for 5 days. The culture medium was replenished daily. (D) The CXCR4 antagonist AMD3100 specifically inhibits SP in the tamoxifen-resistant MCF7(TAM-R) cells in a dose-dependent manner. The cells were cultured in tamoxifen-free growth medium in the presence of inhibitors at indicated concentration for 3 days. The culture medium was replenished daily.

A Dubrovska, et al. Br J Cancer. 2012 June 26;107(1):43-52.
4.
Figure 4

Figure 4. From: CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling.

AhR signalling differentially regulates MCF7(TAM-R) and MCF7 cells. (A) Structure of AhR antagonists SR1 and SR2. (B) Small molecule antagonists of AhR signalling SR1, SR2 and CH-223191could specifically inhibit ALDH-positive MCF7(TAM-R) cells and induce ALDH-positive population in MCF7 cells, (C). The cells were cultured in tamoxifen-free growth medium in the presence of SR1, SR2 and CH-223191at concentration 1 μℳ, 3 μℳ and 3 μℳ, respectively for 5 days. The culture medium was replenished daily. (D) AhR agonist methylchloroanthrene specifically increases ALDH population in MCF7(TAM-R) cells. The cells were cultured in tamoxifen-free growth medium in the presence of methylchloroanthrene at concentration 5 μℳ for 5 days. The culture medium was replenished daily. (E) AhR antagonists SR1 and SR2 specifically increase AhR-depedent expression of LY6E gene in tamoxifen-sensitive MCF7 cells. (F) Preincubation of MCF7(TAM-R) cells with small molecule antagonists of AhR before subcutaneous injection into nude mice significantly delayed tumour growth compared with MCF7 (TAM-R) xenografts treated with DMSO or MCF7 xenografts treated with AhR antagonist. The cells were cultured in tamoxifen-free growth medium in the presence of SR2 at concentration 3 μℳ or DMSO for 5 days. The culture medium was replenished daily.

A Dubrovska, et al. Br J Cancer. 2012 June 26;107(1):43-52.
5.
Figure 3

Figure 3. From: CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AhR signalling.

Inhibition of CXCR4 reduces tamoxifen-resistant tumour growth in vivo and alters AhR signalling. (A) MCF7(TAM-R) xenograft tumours treated with AMD3100 showed more than a twofold decrease in the growth rate compared with a control group. (B) The tamoxifen-sensitive xenograft tumours did not show a significant growth inhibition in response to AMD3100 treatment. (C) Haematoxylin and eosin staining of the xenografts showed regressive MCF7(TAM-R) tumours in AMD3100-treated animals. Two histological sections of two different tumours were analysed for each treatment condition. Representative images are showed. (D) Histological analysis of MCF7(TAM-R) xenograft tumours treated with AMD3100 revealed a decrease in ABCG2 expression as compared with untreated MCF7(TAM-R) xenografts and tumours formed by MCF7 cells. (E) Gene expression analysis revealed the aryl hydrocarbon receptor signalling in top ten networks that are deregulated in MCF7(TAM-R) tumours as compared with MCF7 xenograft tumours. TP53, FOS, PERG, SMARCA4 and HSP90AA1 genes that are involved in AhR signalling network are similarly downregulated in MCF7(TAM-R) tumours treated with CXCR4 inhibitor AMD3100 and tamoxifen and upregulated in MCF7 tamoxifen-sensitive tumours under the same treatment conditions. (F) Microarray results were validated by RT–PCR analysis.

A Dubrovska, et al. Br J Cancer. 2012 June 26;107(1):43-52.

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