CXCR4 activation maintains a stem cell population in tamoxifen-resistant breast cancer cells through AHR signaling

Targeting the estrogen signaling pathway has proved to be of great value in the treatment of human breast cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), is the most widely used antiestrogen. However, only 40-50% of patients with estrogen receptor (ER) positive breast cancer benefit from tamoxifen treatment and 30-50% acquire resistance and the disease progresses. Continuous treatment with conventional therapy may contribute to cancer progression in recurring cancers through the accumulation of drug resistant cancer progenitors. We found that MCF7 tamoxifen-resistant (TAM-R) cells possess a significantly higher proportion of cancer progenitor cells than tamoxifen-sensitive MCF7 cells. Our results indicate that the chemokine receptor CXCR4 plays an important role in the maintenance of cancer progenitors in a tamoxifen-resistant cell line and downregulation of CXCR4 signaling by small molecule antagonists specifically inhibits growth of a stem-like cell population in tamoxifen-resistant tumors both in vitro and in vivo. Whole genome gene expression analysis revealed aryl hydrocarbon receptor (AhR) signaling as one of the top networks that is differentially regulated in MCF7(TAM-R) xenograft tumors treated with the CXCR4 antagonist AMD3100 as compared to MCF7 tumors. Further, small molecule antagonists of AhR signaling specifically inhibit the progenitor population in MCF7(TAM-R) cells suggesting that the aryl hydrocarbon receptor could be a putative target for the treatment of tamoxifen-resistant breast cancers. Introduction transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.

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Dubrovska A, Hartung A, Bouchez LC, Walker JR, Reddy VA, Cho CY, Schultz PG