Zhang Shu, Lei Ping, Liu Xinyi, Li Xiangrong, Walker Kelcey, Kotha Leela, Rowlands Craig, Safe Stephen
Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 Holcombe Boulevard, Houston, Texas 77030, USA.
Endocr Relat Cancer. 2009 Sep;16(3):835-44. doi: 10.1677/ERC-09-0054. Epub 2009 May 15.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the relatively non-toxic selective aryl hydrocarbon receptor (AhR) modulator 6-methyl-1,3,8-trichlorodibenzo-furan (MCDF) induced CYP1A1-dependent ethoxyresorufin O-deethylase activity and inhibited proliferation of seven estrogen receptor (ER) negative breast cancer cell lines. MCDF, TCDD and structurally related 2,3,7,8-tetrachlorodibenzofuran, 1,2,3,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-pentachlorodibenzofuran, and 3,3',4,4',5-pentachlorobiphenyl induced CYP1A1 and inhibited proliferation of BT-474 and MDA-MB-468 cells. In BT474 and MDA-MB-468 cells transfected with a small inhibitory RNA for the AhR, the antiproliferative activity of the chlorinated aromatic compounds was reversed, whereas for MCDF, only partial reversal was observed, suggesting that this compound acts through both AhR-dependent and AhR-independent pathways in these two cell lines. MCDF also inhibited tumor growth in athymic nude mice in which MDA-MB-468 cells were injected directly into the mammary fat pad. These results suggest that the AhR is a potential drug target for treatment of ER-negative breast cancer.
2,3,7,8-四氯二苯并-对-二恶英（TCDD）以及相对无毒的选择性芳烃受体（AhR）调节剂6-甲基-1,3,8-三氯二苯并呋喃（MCDF）可诱导CYP1A1依赖性乙氧基异吩恶唑酮O-脱乙基酶活性，并抑制7种雌激素受体（ER）阴性乳腺癌细胞系的增殖。MCDF、TCDD以及结构相关的2,3,7,8-四氯二苯并呋喃、1,2,3,7,8-五氯二苯并-对-二恶英、2,3,4,7,8-五氯二苯并呋喃和3,3',4,4',5-五氯联苯可诱导CYP1A1，并抑制BT-474和MDA-MB-468细胞的增殖。在转染了针对AhR的小干扰RNA的BT474和MDA-MB-468细胞中，氯化芳香化合物的抗增殖活性被逆转，而对于MCDF，仅观察到部分逆转，这表明该化合物在这两种细胞系中通过AhR依赖性和AhR非依赖性途径发挥作用。MCDF还抑制了无胸腺裸鼠的肿瘤生长，在这些裸鼠中，MDA-MB-468细胞被直接注射到乳腺脂肪垫中。这些结果表明，AhR是治疗ER阴性乳腺癌的潜在药物靶点。
