Background: Many different types of cancer (renal, lung, colorectal, prostate, uterus, breast and pancreatic) have already been associated to polymorphisms of the Renin Angiotensin System (RAS) genes. Angiotensin II (Ang II) is a vasoconstrictor, a mitogen and a angiogenic factor, whereas the angiotensin-(1-7) [Ang-(1-7)] has vasodilator, antiproliferative and anti-angiogenic properties. Classically, Ang II and Ang-(1-7) exert their effects through the AGTR 1-2 and the MAS1 oncogene receptors respectively. The MAS1 receptor expression is associated to lung cancer and the hormone Ang-(1-7) inhibits proliferation in these neoplasias. Moreover, some studies have correlated the MAS1 receptor gene expression to breast cancer. To further test the hypothesis that Ang II and Ang-(1-7) participate in breast carcinogenesis through AGTR2 and MAS1 oncogene receptors respectivelly, we assessed genetic polymorphisms in the 5′-region of the AGTR2 gene (T1247G and A5235G) and in the MAS1 oncogene (C647T) in two groups: breast cancer patients and normal women and their possible associations to breast cancer among Brazilian women. Methods: The genotyping assay was performed through the Custom TaqMan SNP Genotyping assays, probes and primers Assay-by-Design were used for the end-point collection qPCR human SNPs genotyping. Genomic DNA samples were extracted from blood cells of patients with (case) or without breast cancer (control), aged between 26 and 90 years. In the polymorphism T1247G, 428 samples were processed: 263 cases and 165 controls; 429 samples for polymorphism A5235G: 257 cases and 172 controls and 429 samples in polymorphism C647T: 269 cases and 167 controls. Results: The following distribution of genotypes (%)were obtained for the three polymorphisms: T1247G - TT, TG, GG = 84, 13, 03 in case and 81, 18, 1 in control (p = 0,0025); A5235G - AA, AG, GG = 21, 44, 35 in case and 20, 27, 35 in control (p = 0,36); C647T - CC, CT, TT = 64.0, 0.4, 35.6 in case and 52.0, 0.6, 47.4 in control (p = 0,039). Therefore, T1247G and C647T polymorphisms are associated with breast cancer. Conclusions: Our results suggest an association between T1247G AGTR2 and C647T MAS1 oncogene polymorphisms with breast cancer in the Brazilian population. Both polymorphisms are found in the promoter region of these genes, making of these regions possible targets to change the binding of transcription factors that will eventually transcribe these genes and might result in a different cellular behavior when exposed to the same agonist molecule. This being the case, the T1247G and C647T are possible targets for assessing breast cancer risk, while the A5235G is not. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2598. doi:1538-7445.AM2012-2598
Our findings that 17β-estradiol (E2) initiates neoplastic transformation of human breast epithelial cells (HBECs) led us to clarify the relationship between normal breast epithelial cells and cancer stem cells (CSCs). HBECs MCF-10F transformed in vitro by E2 express increased colony efficiency, invasiveness and tumorigenesis in SCID mice and lose ductulogenesis in collagen (The FASEB J 20:1622, 2006). Cancer progression is associated with gene dysregulation and chromosomal aberrations, amplifications and losses. Progressive changes occur from transformed to tumorigenic and tumor-derived cell lines in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface and mesenchymal markers, like fibronectin, vimentin, and N-cadherin (CDH2) during epithelial-mesenchymal transition (EMT) (Cancer Res 67:11147, 2007), while epithelial markers E-cadherin (CDH1), occludin (OCLN), desmoplakin, and cytokeratins progressively decrease. The cell surface molecule CD44+/CD24/low phenotype, a marker for tumor-initiating cells, is significantly increased in tumorigenic and tumor derived cell lines. Loss of ductulogenesis in E2 transformed cells in collagen is reverted by human chorionic gonadotropin (hCG), a hormone that induces differentiation of the breast epithelium. Since hCG binds to the G-protein coupled receptor (GPCR) luteinizing hormone/chorionic gonadotropin receptor (LH/CG-R), and the cytokine IL-8 receptor (CXCR1), which has been shown to be expressed by cells displaying stem cell characteristics, we determined by RT-PCR the content of CXCR1 in MCF-10F cells and tested the effects of recombinant hCG (r-hCG) and of a 15 aminoacid peptide containing the sequence 8l-95 of the hCG beta chain on the expression levels of LH/CG-R and CXCR1 mRNA in MCF-10F cells. MCF-10F cells were daily treated with: 1) 50 IU/ml r-hCG (Ovidrel®, mD-Serono); 2) 20 µM 81-95 peptide (pp81-95), sequence SYAVALSCQCALCRR-NH2 synthesized by aapptec (Louisville, KY), or 3) vehicle only. Cells were harvested for RNA extraction and cell count at 0, 1, 2, 4, 6, 8, 10 and 15 days of treatment. r-HCG and pp81-95 decreased cell growth by 48%. Both compounds up-regulated LH/CG-R expression from 2.2 to 11.7 fold and down-regulated CXCR1 expression by 1.5 to 4.1 fold. Our novel findings that MCF-10F cells express CXCR1 further confirm a CSC characteristic of these cells. Furthermore, the fact that both r-hCG and its peptide downregulate the expression of CXCR1 while upregulating the expression of the LH/CG-R confirm the differentiating effects of hCG and pp81-95, respectively and support the use of this compounds in cancer preventive and therapeutic strategies. Work supported by Grant KG101080 from Susan G Komen for the Cure. (S.M.R. Noronha and S.A.A.C.Noronha internships at BCRL were supported by CAPES process # 4036-09-3 and 2359-09-0 and by FAPESP). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2299. doi:10.1158/1538-7445.AM2011-2299
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