期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 129, 期 2, 页码 331-345出版社
SPRINGER
DOI: 10.1007/s10549-010-1209-0
关键词
Estrogen receptor; Nicotine; Estrogen; Breast cancer; AP1
类别
资金
- National Science Council [NSC 96-2628-B-038-003-MY3(1-3), NSC 98-2320-B-038-006-MY3(1-3), DOH99-TD-C-111-008, NSC 97-2314-B-038-034-MY3(1-3)]
- Cathay Medical Center [96CGH-TMU-05, 97CGH-TMU-02]
The primary aim of this study was to elucidate the role of the estrogen receptor (ER), a transcription factor involved in the nicotine- and 17 beta-estradiol (E2)-mediated up-regulation of alpha 9-nAChR gene expression. A real-time polymerase chain reaction (PCR) assay was used to quantify the alpha 9-nAChR mRNA expression levels of surgically isolated (n = 339) and laser-capture microdissected tissues (ER+ versus ER-, n = 6 per group). Chromatin immunoprecipitation (ChIP) and luciferase-promoter activity assays were used to investigate the ER-mediated transcriptional regulation of alpha 9-nAChR gene expression. We observed that breast tumors with higher alpha 9-nAChR mRNA expression levels (i.e., a mean fold ratio in the tumor/normal-paired samples of greater than tenfold) were associated with the lowest 5-year disease-specific survival rate (50%, dead/alive = 4/4, total = 8 patients, P = 0.006), in contrast to breast tumors with low levels (i.e., a mean fold ratio of less than onefold) of alpha 9-nAChR expression (88%, dead/alive = 3/22, total = 25 patients). Furthermore, higher alpha 9-nAChR mRNA expression levels were preferentially detected in ER+ tumor tissues in comparison to ER- tumor tissues (ER+ versus ER- patients: n = 160 vs. 72; mean fold ratios of alpha 9-nAChR expression = 11 +/- A 3 vs. 6.7 +/- A 2.3 fold, respectively). In vitro promoter-binding assays demonstrated that the ER is a major transcription factor that mediates nicotine- and E2-induced up-regulation of alpha 9-nAChR gene expression in MCF-7 cells. In conclusion, our data indicate that the ER plays a central role in mediating alpha 9-nAChR gene up-regulation in response to either nicotine or E2 stimulation.
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