The Murine Double Minute 2 (MDM2) amplification or overexpression has been found in many tumors with high metastatic and angiogenic ability. Our experiments were designed to explore the impact of MDM2 overexpression, specifically on the levels of angiogenesis-related genes, which can also play a major role in tumor propagation and increase its metastatic potential. In the present study, we have used the human angiogenesis RT2 profiler PCR array to compare the gene expression profile between LNCaP and LNCaP-MST (MDM2 transfected) prostate cancer cells, along with LNCaP-MST cells treated with Nutlin-3, an MDM2 specific inhibitor. As a result of the overexpression of MDM2 gene in LNCaP-MST (10.3-fold), Thrombospondin 1 (THBS1), Tumor necrosis factor alpha (TNF-α) and Matrix metallopeptidase 9 (MMP9) were also found to be significantly up-regulated while genes such as Epiregulin (EREG), Tissue inhibitor of metalloproteinases 1 (TIMP1) were down-regulated. Also, we determined the total MMP activity and MMP9 expression in LNCaP, LNCaP-MST and SJSA-1 cells. Our results indicated that MDM2 level is positively correlated with MMP activity and MMP9 secretion. Our findings offer strong supporting evidence that MDM2 can impact growth and metastatic potential of cancer cells through tilting the balance towards pro-angiogenic mechanisms.

The Notch signaling pathway is an evolutionarily conserved cell signaling pathway. It plays a central role in cell fate decisions and differentiation. The bioavailability of sclareol has been widely studied due to its anti-carcinogenic and antioxidant effects. However, chemo preventive effects of sclareol on notch signaling in 7, 12-dimethylbenz [a] anthracene (DMBA) induced hamster buccal pouch(HBP) carcinogenesis remain to be fully elucidated. In the present study, tumors were induced by applying 0.5% DMBA topically to HBP thrice a week for 14 weeks and sclareol was orally administered at a dose of 20mg/kg body weight on alternate days of DMBA painting. We analyzed expression of Notch signaling in DMBA induced oral squamous cell carcinoma (OSCC) in experimental oral carcinogenesis and inhibition of notch signaling by sclareol. This study thus observed up regulation of Notch1, Notch2, Jagged1, Hes1 and Hey1 in DMBA alone induced hamsters. Furthermore, oral administration of sclareol led to reduced Notch1, Notch2 activation and expression of Jagged-1 and its downstream targets of Hes-1 and Hey-1 in tumor bearing hamsters. In addition, sclareol treatment increased pro-apoptotic and decreased anti-apoptotic proteins survival indicating apoptosis through activation of caspase 3, and promoting cell death by dysregulation of cyclin D1 levels in tumor bearing hamsters. Immunohistochemical examination showed that Notch intracellular domain accumulates in the nucleus of cells in DMBA induced hamster buccal pouch carcinogenesis, and Jagged1 was found to be dysregulated in sclareol treated tumor animals. In conclusion, the results provide an important new insight of Notch signaling pathway for a potential therapeutic target for oral cancer. Citation Format: Aiyavu Chinnaiyan, Anandhi Nallu, Suresh Kathiresan. Sclareol induces apoptosis and inhibits notch signaling in hamster oral carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 10.

Introduction: The concept that some dietary proteins may prevent the onset or spread of hepatocellular carcinoma (HCC) was tested in mice model in this study. Experimental procedure: The animals were divided into seven groups, with six mice in each based on diet treatment. Group I- Control, Group II- Diethylnitrosamine (DEN) alone treated, Group III- Soy protein treated, Group IV- Garlic protein treated, Group V- Coconut protein treated, Group VI- Whey protein treated, Group VII- Casein treated. The animals were acclimatized in their respective diets for 60 days. On the 60th day, DEN was given intraperitoneally as a single dose (120 mg/kg body weight) in saline, to each animal in groups from II to VII, and was followed by weekly subcutaneous injections of carbon tetrachloride for four weeks at individual doses of 3 mL/kg body weight to induce hepatocellular carcinoma. Group I and II, were continued on the normal diet and the groups III to VII were fed their respective diets for 120 days. Thus Group II consisted of animals that were HCC-induced with DEN. Animals belonging to groups III-VII were pre and post treated with different protein isolates from specific sources. At the end of the experimental period, ie. on day 120, the mice were sacrificed and blood for serum separation and liver sample for biochemical analysis were collected. Alpha-fetoprotein, ornithine decarboxylase, tumor necrosis factor-β, gamma-glutamyl transpeptidase, aspartate transaminase, alanine transaminase, alkaline phosphatase, and antioxidant enzyme activities of superoxide dismutase, catalase, and glutathione peroxidase were assayed both in serum and in liver homogenate. Summary of data: The levels of alpha-fetoprotein, ornithine decarboxylase, tumor necrosis factor-β, gamma-glutamyl transpeptidase, aspartate transaminase, alanine transaminase and alkaline phosphatase were elevated and the antioxidant enzymes were significantly (P<0.05) decreased in diethylnitrosamine alone treated mice. The activities of marker enzymes and antioxidant enzymes were significantly (P<0.05) restored in the animals treated with various protein isolates. Histological sections of liver of DEN alone-administered group had gross structural alterations in comparision with control mice. The cytoplasmic material was compact with clear cell foci in soy protein, garlic protein and coconut protein pre and post-treated groups. In addition, the level of Immunoglobulin E (IgE) expression was estimated as a measure of allergic reaction. Garlic protein treated and whey protein treated animals had high values of IgE. Conclusions: The overall results confirm the protective role of these protein isolates. Among them the soy protein, garlic protein and coconut protein were better than others in preventing hepatocellular carcinoma like condition. 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 1620. doi:1538-7445.AM2012-1620

Studies in different populations worldwide have demonstrated that germ line mutations in BRCA1 and BRCA2 account for the majority of hereditary breast and ovarian cancers. In addition, polymorphic variants in these genes have been implicated in an increased breast and ovarian cancer risks. Indeed, it has been known that the germ line mutations in the BRCA1 gene can strikingly increase the life time risk of ovarian cancer by 15-30%. Among BRCA mutations the Q356R polymorphism is a variant causing the amino acid switch from glutamine (Q) to arginine (R) in the putative functional domain of the protein. The present study was carried out to assess the frequency of Q356R polymorphism in BRCA1 gene among Jamaican ovarian cancer patients, since there is lack of data for this population pertaining to this polymorphism. For this analysis the ovarian cancer samples were collected from 23 Jamaican women with 21 benign and 2 malignant tumors. The genomic DNA of cancer samples was extracted and the purity of the DNA was analyzed prior to polymorphism determination. Polymerase chain reaction was performed using the DNA of cancer patients as a template with the primers specific for BRCA1 gene. The Q356R polymorphism status within BRCA1 gene was analyzed through restriction enzyme digestion. The undigested or partially digested arginine (R) coding allele was seen as a band at 211 bp of length, whereas the glutamine (Q) alleles represented by the digestion products were seen at 134 and 77 bp length. The incomplete digestion of R allele indicates a high risk and the digested Q alleles signify the medium or low risk category. Genotyping analyses were performed in all 23 cases using the restriction fragment length analysis. Out of 23 samples, 22 showed digestion fragments of 134 bp and 77 bp, remaining one was partially digested and showed a 211 bp band. Among the samples analyzed the percentage of R allele was (4.34%) and the Q alleles were (95.65%). Our current analysis indicates that the QR genotype frequency for Jamaican women with non-malignant ovarian tumors is only 0.04. However, the QR genotype frequency for Jamaican women with malignant ovarian cancer appears to be 0.5. Thus, functional polymorphisms in BRCA1 might be postulated to be more likely affecting ovarian cancer risk than those in BRCA2. Though the frequency of R allele is only 4.3% in Jamaican population, this polymorphism seems to correlate very well with the malignant status of the tumor. Therefore, patients with this polymorphism can be selected for more aggressive surveillance and therapeutic options. The results presented here are from a small population of Jamaican women with ovarian tumors but further validation of this conclusion can be obtained by conducting a study with larger population of patients (The authors would like to thank the Royal Dames of Cancer Research Inc., Ft. Lauderdale, FL, for their generous support). Citation Format: Aiyavu Chinnaiyan, Colleen Salmon, Thiagarajan Venkatesan, Arkene Levy, Sivanesan Dhandayuthapani, Appu Rathinavelu. Analysis of Q356R polymorphism in BRCA1 gene of Jamaican ovarian cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 259. doi:10.1158/1538-7445.AM2014-259

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