Breast cancer is the most common cancer in females worldwide. RIP140 was one of the first proteins recognized as nuclear receptor transcriptional cofactor which interacts with several nuclear receptors. RIP140 plays a central role in metabolic tissues with multifunctional co-regulation. It is an essential protein required for energy homeostasis and mammary gland development. RIP140 has been found to be involved in development of breast cancer in response to estrogen. RIP140 is recruited by estrogen receptors in the presence of estrogen. Increasing levels of estrogen and RIP140 stimulate their transcription and regulate proliferation and differentiation of mammary glands. We hypothesize that RIP140 may be over expressed in breast cancer and may be correlated with clinicopathological features and may thus serve as a possible new prognostic marker in breast cancer. In our study, the correlation between the RIP140 expression and survival was investigated by immunohistochemistry (IHC), and analyzed by Pearson’s chi-square and Kaplan Meier analysis. Cox regression analysis was performed to examine the relationship between clinic-pathological parameters and the survival. Total of one hundred and eighteen breast cancer samples were examined for the RIP140 staining localization in breast cancer cells. Our results showed that the IHC staining of RIP140 was observed in both cytoplasm and nucleus of breast cancer cells. The ER positive staining was significantly correlated with high nuclear expression of RIP140, but not RIP140 cytoplasmic expression. Thus nuclear RIP140 expression was examined for correlation with other clinic-pathological features and patient survival. The correlation between nuclear RIP140 expression and clinic-pathological features by Pearson’s chi-square test showed that high RIP140 nuclear staining score is associated with ER positive status (p-value=0.041) and tumor stage (p-value=0.008). Kaplan Meier test shown that nuclear RIP140 expression is not significant associated with either overall survival or disease-specific survival. However, a trend of high nuclear RIP140 score was observed with poorer overall and disease-specific survival though not statistically significant. To conclude, our results suggest RIP140 is not a useful prognostic marker for breast cancer. Further investigation with larger sample size is necessary to improve the statistical significance of the test. / published_or_final_version / Pathology / Master / Master of Medical Sciences

No description available.

The transition from normal mammary development to the formation of aberrant cancerous tissues requires numerous mutations to occur. These alterations allow cancer cells to evade the usually strictly controlled pathways of survival, proliferation and self-renewal. The cell of origin for most tumours remains unknown but evidence that a sub-population of stem-like cells, termed cancer initiating cells, exists within solid cancers is strong.

No description available.

Sirtuins (Silent Information Regulator Two (SIR2) protein) are NAD-dependent protein deacetylases, originally discovered in yeast. Sirtuins play a critical role in the regulation of different cellular processes involving aging, chromatin silencing and cellular differentiation. SIRT6 is a member of Sirtuins and plays a role in regulation of DNA repair and suppression of genomic instability. Many studies have shown SIRT6 to be associated with diseases of aging, including cancer. The finding by our collaborator that SIRT6 expression was found in chemotherapy-resistant breast cancer cell lines stimulated this study which aims to explore the role of SIRT6 expression as a prognostic marker in breast cancer. One hundred and eighteen breast cancer samples in tissue microarray blocks were examined for SIRT6 expression by immunohistochemistry. As SIRT6 expression is predominantly located in the nucleus but with a small fraction in cytoplasm, the calculation of nuclear or cytoplasmic localization scores were divided by total localization scores to increase accuracy. The nuclear localization scores represent the SIRT6 expression in breast cancer. Statistical analysis was performed using SPSS software. SIRT6 overexpression in the nucleus was significantly associated with poorer overall survivals (p=0.018) while low cytoplasmic expression of SIRT6 was also associated with poorer overall survivals (p=0.014). There was no relationship between SIRT6 expression and disease-specific survivals. By multivariate analysis, SIRT6 expression was an independent predicator of poorer overall survivals. These results suggest that SIRT6 overexpression induces apoptosis in cancer cells through deacetylation of transcription factor p65. SIRT6 interacts with and deacetylates p65 to activate nuclear factor kappa B gene linked to cancer. Also high levels of SIRT6 were associated with resistance to paclitaxel and epirubicin inMCF-7 breast cancer cell lines. This provides evidence that Sirt6 is an important prognostic marker and therapeutic target for breast cancer. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Breast cancer is the most frequent malignancy in women. Recent studies have proposed that sirtuin 1 (SIRT1) may play a certain role in the tumorgenesis and disease progression of cancer. Therefore, in this study, we demonstrate the localization of SIRT1 in the breast cancer cells by immunohistochemistry method and try to correlate the expression level of SIRT1 with various clinical-pathological parameters as well as the survival time of breast cancer patients. One hundred and eighteen breast cancer cases, arrayed as dual‐cores, were studied in the tissue microarray blocks for their SIRT1 nuclear and cytoplasmic stain. The expression of SIRT1 is found in over 95% of the tumor samples. Although the active functioning site of SIRT1 is known to be mainly the nucleus, both nuclear and cytoplasmic localization score are assessed separately for SIRT1 expression for more accurate statistically analysis. By bi‐variate Pearson correlation analysis, high nuclear localization of SIRT1 is significantly correlated with low tumor grade (p=0.006) and ER (p=0.001) and PR positive status (p=0.044). Moreover, the cytoplasmic localization score of SIRT1 shows positive correlation with tumor grade (p=0.010). The relationship of SIRT1 expression and survival time of breast cancer patient was studied by Kaplan‐Meier analysis. Despite a marginal fail in obtaining a statistically significant result, the trend in survival curve clearly indicated that nuclear localization of SIRT1 is associated with a poorer overall survival (p=0.052). Although the pathway of how SIRT1 affects the survival of breast cancer patient is still unknown, many studies suggested that it is largely due to the deacetylated inactivation of p53 tumor suppressor protein by SIRT1. In conclusion, we propose that nuclear localization of SIRT1 can be a potential prognostic factor of breast cancer patients. / published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Breast cancer comprises of 22.9% of all cancers worldwide in females. In the year 2008, it has caused 458,503 deaths worldwide. De-regulation of transcription factors has been shown to play an important role in the progression of breast cancers. Snail and TWIST genes have been found to promote epithelial-mesenchymal transition (EMT). It has been suggested that the level of expression of each of these genes correlates with poor prognosis in different types of solid tumors. For breast cancer, the up-regulation of Snail was associated with recurrence and higher tumor grade, while the up-regulation and up-regulation of TWIST was associated with shorter survival and metastatic development. However, in recent studies conflicting results have been observed. Our collaborator had analyzed mRNA expression data obtained from the Gene Expression Omnibus (GEO) database together with patient survival data from the breast cancer cohort datasets, and found that expression of Snail when stratified against TWIST expression levels or vice versa, gave more significant association with survival than when expression levels of Snail or TWIST was considered on their own. To investigate whether these findings could be demonstrated at a protein level, we performed imrnuno-histochemisty analysis on breast cancer samples in tissue microarray blocks. Nuclear and cytoplasmic scores of TWIST were successfully assessed separately in 114 invasive breast cancer patients. The Snail scores were obtained from previous studies. As Snail and TWIST are both transcription factors, nuclear expression of each was examined for correlation of Snail and TWIST with pathological features and patient survival. Our results showed that nuclear Snail expression did not correlate with survival (p=0.498) but when stratified with nuclear TWIST, high levels of nuclear Snail expression associated with poorer survival in patients with low nuclear TWIST expression (p=O.2l2), though not statistically significant which agreed with the mRNA results of our collaborator. For nuclear TWIST expression, association with survival was in reverse from that of the mRNA findings. Low expression levels of TWIST mRNA was associated with shorter survival, however immuno-histochemistry showed that high levels of nuclear TWIST expression marginally correlated with poorer survival (p=O.079). Low levels of cytoplasmic TWIST expression on the other hand, correlated with poorer survival in patients (p=O.024), and when stratified against high nuclear Snail, expression was associated with shorter survival (p=O.022), which is in keeping with mRNA findings. The results show that Snail and TWIST expression gave more prognostic value when considered together than when considered individually, which suggests that Snail and TWIST might be functionally similar in the promoting of EMT mediated breast. It also highlights the importance of nuclear and cytoplasmic localization by immuno-histochemistry in evaluating results and in assessing its role in promoting breast cancer progression. In conclusion Snail and TWIST should be considered together for prognostication of breast cancer as they may complement each other in predicting the progression of the disease. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Breast cancer is the leading malignancy among Asian women, which often have a young disease onset pattern. Germline mutation in high-penetrance breast cancer susceptibility genes are known to play an important role in early disease onset, but only 5-10% cases are associated with mutations in BRCA1 or BRCA2 gene. By contrast, common variants might also have deleterious effect in breast cancer development. A BRCA2 coding SNP rs1799944 (N991D) was found to have no association with breast cancer risk among Hong Kong Chinese population, but significantly confers a better disease-free survival in the breast cancer patients. In this study, the relevance of this association was further verified by using an enlarged sample pool of Hong Kong Chinese breast cancer patients. A total of 483 Hong Kong Chinese breast cancer subjects were unselectively recruited between 1976 and 2011. SNP N991D genotype of patients was determined by Taqman allelic discrimination genotyping assay. Pearson’s Chi-Square and logistic regression were used to assess the association between the SNP genotypes and breast cancer disease characteristics. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between the SNP genotypes and overall survival as well as disease-specific survival of the patients. Of the 449 breast cancer patients successfully genotyped, 16.9% had heterozygous AG genotype and 0.4% had rare homozygotes GG genotype. The variant allele G had a MAF of 8.91% among Hong Kong Chinese breast cancer patients. Patients harboring the SNP N991D variant allele G had longer disease-free survival period compared to the non-carriers (HR = 0.28; 95% CI: 0.09 – 0.92; p=0.036), which was confounded by patients’ local and/or distant metastasis status at diagnosis stage (HR=3.00; 95% CI: 1.57 – 5.74; p=0.001). Although N991D carriers also had a better overall survival pattern than the non-carriers, the difference between them was not statistically significant. Moreover, the association of SNP N991D variant allele G carriers with a lower disease recurrence rate (OR= 0.27; 95% CI: 0.82 - 0.90; p=0.023) was owing to the association of the variant with fewer distant metastases (OR = 0.11; 95% CI: 0.02 – 0.83; p=0.010) but not the local relapse status (OR= 0.38; 95% CI: 0.85 – 1.67; p=0.182) of the clinical outcome when comparing to the non-carriers. In conclusion, the missense BRCA2 N991D SNP has indicated an association with better clinical outcome as well as disease-free survival in Hong Kong Chinese breast cancers. / published_or_final_version / Pathology / Master / Master of Medical Sciences

No description available.