Abstract
Identification of new molecular targets for the treatment of breast cancer is an important clinical goal, especially for triple-negative breast cancer, which is refractory to existing targeted treatments. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, and thus may be a potential anticancer target. To investigate the AhR as an anticancer target, we conducted a small molecule screen to discover novel AhR ligands with anticancer properties. We identified raloxifene, a selective estrogen receptor (ER) modulator currently used in the clinic for prevention of ER-positive breast cancer and osteoporosis in post-menopausal women, as an AhR activator. Raloxifene directly bound the AhR and induced apoptosis in ER-negative mouse and human hepatoma cells in an AhR-dependent manner, indicating that the AhR is a molecular target of raloxifene and mediates raloxifene-induced apoptosis in the absence of ER. Raloxifene selectively induced apoptosis of triple-negative MDA-MB-231 breast cancer cells compared with non-transformed mammary epithelial cells via the AhR. Combined with recent data showing that raloxifene inhibits triple-negative breast cancer xenografts in vivo (Int J Oncol. 43(3):785-92, 2013), our results support the possibility of repurposing of raloxifene as an AhR-targeted therapeutic for triple-negative breast cancer patients. To this end, we also evaluated the role of AhR expression on survival of patients diagnosed with breast cancer. We found that higher expression of the AhR is significantly associated with increased overall survival and distant metastasis-free survival in both hormone-dependent (ER-positive) and hormone-independent (ER and progesterone receptor (PR)-negative) breast cancers. Together, our data strongly support the possibility of using the AhR as a molecular target for the treatment of hormone-independent breast cancers.
Highlights
The role of the aryl hydrocarbon receptor (AhR) in carcinogenesis continues to evolve
Apoptosis induced by raloxifene was significantly increased in vT{2} cells compared with C4 cells (Figure 4d). These results indicated that induction of apoptosis by raloxifene in mouse hepatoma cells was significantly dependent on the activity of both AhR and AhR nuclear translocator (ARNT)
While the AhR has been studied in the past as the mediator of TCDD toxicity[1,10,40,41] as well other environmental carcinogens, recent studies strongly suggest that the AhR has the potential to be an effective target for cancer
Summary
The role of the AhR in carcinogenesis continues to evolve. The prototypical AhR ligand 2,3,7,8-Tetrachlorodibenzo-pdioxin (TCDD) acts as a tumor promoter in rodent models;[2,3,4,5] there is no direct evidence that AhR promotes tumorigenesis in humans. Identification of activators of AhR-mediated transcription from existing FDA-approved drugs may significantly expedite this goal by identifying new indications, thereby re-tooling old Received 17.4.13; revised 04.11.13; accepted 05.11.13; Edited by RA Knight drugs for a new anticancer target. Based on our small molecule-screening results, we investigated whether raloxifene had anticancer effects mediated through the AhR, and found that it induces apoptosis in an AhR-dependent manner. Our results suggest that the AhR can be targeted to induce apoptosis in ER-negative breast cancer cells, which may have important clinical implications for the treatment of both hormoneindependent and triple-negative breast cancers expressing the AhR
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