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- Title
Phthalates induce proliferation and invasiveness of estrogen receptor-negative breast cancer through the AhR/HDAC6/c-Myc signaling pathway.
- Authors
Tsung-Hua Hsieh; Cheng-Fang Tsai; Chia-Yi Hsu; Po-Lin Kuo; Jau-Nan Lee; Chee-Yin Chai; Shao-Chun Wang; Eing-Mei Tsai
- Abstract
The environmentally present group of chemical phthalates, or phthalate esters, has been recognized as a rising threat to public health, including cancer. While most studies have addressed the estrogenic effects of phthalates in malignancies of the breast and the prostate, little is known about their role in the etiology of hormone-independent cancer. Here we show that treatments with the phthalates n-butyl benzyl phthalate (BBP) and dibutyl phthalate (DBP) at 1 µM induced proliferation (BBP, 3.2-fold; DBP, 3.2-fold), migration (BBP, 2.6-fold; DBP, 2.6-fold), invasion (BBP, 2.7-fold; DBP, 3.1-fold), and tumor formation (EC50: BBP, 0.12 µM; DBP, 0.22 µM) in estrogen receptor (ER)-negative breast cancer cells (MDA-MB-231). We further demonstrate that phthalates stimulated the cell surface aryl hydrocarbon receptor (AhR) and triggered the downstream cyclic AMP (cAMP)-PKACREB1 signaling cascade. The pathway led to increased expression of HDAC6, which facilitated nuclear assembly of the β-catenin-LEF1/TCF4 transcriptional complex and transactivation of the c-Myc oncogene. This nongenomic pathway emanated from the phthalate-induced AhR promoted tumorigenesis of ER-negative breast cancer. Collectively, our findings revealed a novel oncogenic mechanism of phthalates in breast cancer independent from their estrogenic activities.
- Subjects
PHTHALATE esters; CANCER; ESTROGEN; HYDROCARBONS; ORGANIC compounds
- Publication
FASEB Journal, 2012, Vol 26, Issue 2, p778
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.11-191742