title: Angiotensin II receptor type 1 blockers suppress the cell proliferation             effects of angiotensin II in breast cancer cells by inhibiting AT1R signaling.
abstract: Chronic stress and a high-fat diet are well-documented risk factors associated with the renin-angiotensin system in the development of breast cancer. The angiotensin II type 1 receptor (AT1R) is a novel component of the renin-angiotensin system. Several recent studies have focused on the function of AT1R in cell proliferation during cancer development. Thus, we hypothesized that angiotensin II (Ang Ⅱ) can promote proliferation of breast cancer via activated AT1R; the activation of AT1R may play an important role in promoting breast cancer growth, and AT1R blocker (ARB) may suppress the promotional effect on proliferation by antagonizing AT1R. The expression level of AT1R was found to be significantly upregulated in breast cancer cells by immunohistochemistry, but no correlation between AT1R expression and ER/PR/Her-2 expression was observed. The AT1R(+)-MCF-7 cell line exhibited high expression of AT1R protein, and we generated the AT1R(-)-MCF-7 cell line using RNA interference. ARBs, and in particular irbesartan, effectively inhibited the effects of Ang II on cell proliferation, cell cycle development and downstream AT1R signaling events, including the activation of the Ras-Raf-MAPK pathway and the transcription factors NF-κB and CREB. Irbesartan also significantly altered p53, PCNA and cyclin D1 expression, which was also influenced by activated AT1R in AT1R(+)-MCF-7 cells. These results suggest that ARBs may be useful as a novel preventive and therapeutic strategy for treating breast cancer.
authors.affiliation: Department of Oncosurgery, First Αffiliated Ηospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Du
authors.forename: Jiang
authors.initials: J
authors.lastname: Feng
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Sun
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D005260:Female; D006801:Humans; D000077405:Irbesartan; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C544065:AGTR1 protein, human; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D016328:NF-kappa B; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D016159:Tumor Suppressor Protein p53; D000804:Angiotensin II; D019938:Cyclin D1; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D000077405:Irbesartan