Journal
FASEB JOURNAL
Volume 26, Issue 2, Pages 778-787Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.11-191742
Keywords
environmental hormone; aryl hydrocarbon receptor; histone deacetylase 6; ER-negative; nongenomic
Categories
Funding
- National Science Council, Taiwan [MY3, 99-2628-B-037-009-MY3]
- Ministry of Education, Taiwan [KMU-EM-99-3]
- Kaohsiung Medical University (Hospital) [KMUH 97-7R08, KMUH 98-8R19, KMUH 99-9I04, KMUH 99-9R30, KMUER-004]
- Susan Komen Breast Cancer Research Award [KG080540]
- University of Cincinnati
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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 mu M 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 mu M; DBP, 0.22 mu M) 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)-PKA-CREB1 signaling cascade. The pathway led to increased expression of HDAC6, which facilitated nuclear assembly of the beta-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.-Hsieh, T.-H., Tsai, C.-F., Hsu, C.-Y., Kuo, P.-L., Lee, J.-N., Chai, C.-Y., Wang, S.-C., Tsai, E.-M. Phthalates induce proliferation and invasiveness of estrogen receptor-negative breast cancer through the AhR/HDAC6/c-Myc signaling pathway. FASEB J. 26, 778 -787 (2012). www.fasebj.org
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