Breast cancer is the most common cancer among females and it is the leading cause of death in mid-age women. Epidemiological studies indicate that Asian women have a lower incidence of breast cancer compared with their counterparts in the West, which soy consumption has been suggested as a contributory factor. Soy and soy-based food contain a rich amount of phytoestrogens, which are suggested to be protective against cancer. Cyclooxygenase (COX) is the rate-limiting enzyme for the conversion of arachidonic acid to prostaglandins. Recent studies have revealed that up-regulation of cyclooxygenase-2 (COX-2), an isoform of COX, plays an important role in tumorigenesis and metastasis. COX-2 may facilitate carcinogenesis in a number of means, may include altering cell proliferation and apoptosis, enhancing angiogenesis and suppressing immune surveillance. Clinical examinations of breast cancer specimens indicated that COX-2 is overexpressed. In the present study, we investigated the effect of flavonoids on COX-2 expression in human breast cells. / Our results showed that daidzein and its metabolite eqoul, genistein, butein, isoliquiritigenin (ILN) and apigenin could inhibit phorbol 12-myristate 13-acetate (PMA)-induced COX-2 expression in breast cells MCF-7 and MCF-10A. The inhibitory effects were in concentration-dependent manners. Real-time PCR and western blot analysis showed that the flavonoids suppressed the induced mRNA and protein expression. Suppression could be observed in concentration as low as 0.1 muM. Luciferase reporter assay indicated that the inhibition was at the gene transactivation level. Further investigation using truncated hCOX-2 promoter plasmids revealed that the AP-1 site (-67/-61) and cyclic AMP response element (CRE) site (-59/-53) on hCOX-2 promoter were responsible for the suppression. Electrophoretic mobility shift assay results further confirmed that the flavonoids acted through inhibiting AP-1/CREB DNA binding to suppress the expression. / To examine the possible upstream signal transduction pathways involved, inhibitors of protein kinase A (PKA), protein kinase (PKC) and mitogen activated protein kinase (MAPK) were employed. Reporter gene assay revealed a possible involvement of ERK1/2 MAP kinase in AP-1 and/or CRE activation of hCOX-2 promoter. Taken together, these results suggested that the phytochemicals down-regulated PMA-induced COX-2 expression by counteracting AP-1 and CRE sites via the modulation of MAPK pathway. The findings might have significant implications in the chemopreventive and chemotherapeutic applications of flavonoids in breast cancer. / Lau, Tak Yi. / "December 2007." / Adviser: Lai Kwok Leung. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4734. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 142-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344139 |
| Date | January 2007 |
| Contributors | Lau, Tak Yi., Chinese University of Hong Kong Graduate School. Division of Biochemistry. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xvi, 164 p. : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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