Article

Aryl Hydrocarbon Receptor Activation during Pregnancy, and in Adult Nulliparous Mice, Delays the Subsequent Development of DMBA-Induced Mammary Tumors

Department of Pharmaceutical Sciences, Washington State University, Pullman, WA, USA.
International Journal of Cancer (Impact Factor: 5.01). 04/2011; 128(7):1509-23. DOI: 10.1002/ijc.25493
Source: PubMed

ABSTRACT 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However, with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, 7,12-dimethylbenz[a]anthracene (DMBA) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a 4-week delay in tumor formation relative to controls, and they had a lower tumor incidence throughout the 27-week time course. The same results were obtained in nulliparous mice given TCDD and DMBA on the same schedule. We next addressed whether the delayed tumor incidence was a reflection of decreased tumor initiation, by testing the formation of DMBA-DNA adducts and preneoplastic lesions, induction of cytochrome P450s, and cell proliferation. None of these markers of tumor initiation differed between vehicle- and TCDD-treated animals. The expression of CXCL12 and CXCR4 was also measured to address their possible role in tumorigenesis. Taken together, our results suggest that AhR activation by TCDD slows the promotion of preneoplastic lesions to overt mammary tumors.

0 Followers
 · 
116 Views
  • Source
    • "This TCDD exposure paradigm was chosen in order to provide a preconditioning period for tissue at both the primary tumor site and at secondary sites for metastasis because the 4T1.2 tumors grow and metastasize very rapidly. Additionally, in previous studies, we found that pretreatment with TCDD delayed the onset of primary mammary tumors in a different tumor model (Wang et al., 2011). The half-life of TCDD in mice is ~1 week (Gasiewicz et al., 1983). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment with aryl hydrocarbon receptor (AhR) agonists can slow or reverse the growth of primary mammary tumors in rodents, which has fostered interest in developing selective AhR modulators for treatment of breast cancer. However, the major goal of breast cancer therapy is to inhibit metastasis, the primary cause of mortality in women with this disease. Studies conducted using breast cancer cell lines have demonstrated that AhR agonists suppress proliferation, invasiveness, and colony formation in vitro; however, further exploration using in vivo models of metastasis is warranted. To test the effect of AhR activation on metastasis, 4T1.2 mammary tumor cells were injected into the mammary gland fat pad of syngeneic Balb/c mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Primary tumor growth was monitored for 4 weeks, at which time metastasis was determined. TCDD treatment suppressed metastasis by approximately 50%, as measured both in the lung and in mammary glands at sites distant from the primary tumor. Primary tumor growth was not suppressed by TCDD exposure nor was proliferation of 4T1.2 cells affected by TCDD treatment in vitro. Taken together, these results suggest that the protective effect of AhR activation was selective for the metastatic process and not simply the result of a direct decrease in tumor cell proliferation or survival at the primary site. These observations in immunologically intact animals warrant further investigation into the mechanism of the protective effects of AhR activation and support the promise for use of AhR modulators to treat breast cancer.
    Toxicological Sciences 09/2011; 124(2):291-8. DOI:10.1093/toxsci/kfr247 · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer stem cells (CSCs) have increased resistance to cancer chemotherapy. They can be enriched as drug-surviving CSCs (D-CSCs) by growth with chemotherapeutic drugs, and/or by sorting of cells expressing CSC markers such as aldehyde dehydrogenase-1 (ALDH). CSCs form colonies in agar, mammospheres in low-adherence cultures, and tumors following xenotransplantation in Scid mice. We hypothesized that tranilast, a non-toxic orally active drug with anti-cancer activities, would inhibit breast CSCs. We examined breast cancer cell lines or D-CSCs generated by growth of these cells with mitoxantrone. Tranilast inhibited colony formation, mammosphere formation and stem cell marker expression. Mitoxantrone-selected cells were enriched for CSCs expressing stem cell markers ALDH, c-kit, Oct-4, and ABCG2, and efficient at forming mammospheres. Tranilast markedly inhibited mammosphere formation by D-CSCs and dissociated formed mammospheres, at pharmacologically relevant concentrations. It was effective against D-CSCs of both HER-2+ and triple-negative cell lines. Tranilast was also effective in vivo, since it prevented lung metastasis in mice injected i.v. with triple-negative (MDA-MB-231) mitoxantrone-selected cells. The molecular targets of tranilast in cancer have been unknown, but here we demonstrate it is an aryl hydrocarbon receptor (AHR) agonist and this plays a key role. AHR is a transcription factor activated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polycyclic aromatic hydrocarbons and other ligands. Tranilast induced translocation of the AHR to the nucleus and stimulated CYP1A1 expression (a marker of AHR activation). It inhibited binding of the AHR to CDK4, which has been linked to cell-cycle arrest. D-CSCs expressed higher levels of the AHR than other cells. Knockdown of the AHR with siRNA, or blockade with an AHR antagonist, entirely abrogated the anti-proliferative and anti-mammosphere activity of tranilast. Thus, the anti-cancer effects of tranilast are AHR dependent. We show that tranilast is an AHR agonist with inhibitory effects on breast CSCs. It is effective against CSCs of triple-negative breast cancer cells selected for anti-cancer drug resistance. These results suggest it might find applications in the treatment of breast cancer.
    PLoS ONE 11/2010; 5(11):e13831. DOI:10.1371/journal.pone.0013831 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is still no consensus on who or what caused the financial crisis which engulfed the world, beginning in the summer of 2007. A huge number of suspects have been identified, from greedy investment bankers, through feckless borrowers, dilatory regulators and myopic central bankers to violent video games and high levels of testosterone among the denizens of trading floors. There is not even agreement on whether the crisis shows a need for more government intervention in markets, or less: some maintain that government encouragement of home ownership lay at the heart of the problem in the US, in particular. In The Financial Crisis Howard Davies charts a course through these arguments, and the evidence advanced for each of them. The reader can thereby assess the weight to be attached to each, and the likely effectiveness of the remedies under development.
Show more