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Phthalates induce proliferation and invasiveness of estrogen receptor‐negative breast cancer through the AhR/HDAC6/c‐Myc signaling pathway
Author(s) -
Hsieh TsungHua,
Tsai ChengFang,
Hsu ChiaYi,
Kuo PoLin,
Lee JauNan,
Chai CheeYin,
Wang ShaoChun,
Tsai EingMei
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-191742
Subject(s) - aryl hydrocarbon receptor , transactivation , estrogen receptor , cancer research , phthalate , dibutyl phthalate , breast cancer , signal transduction , chemistry , medicine , carcinogenesis , endocrinology , oncogene , cancer , biology , cell cycle , transcription factor , biochemistry , organic chemistry , gene
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 (EC 50 : 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)‐PKA‐CREB1 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 phthalateinduced 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