Breast cancer is the second leading cause of mortality among women in the US. A contributing factor to such dire statistics is that conventional therapies are all too often compromised due to tumor relapse. Clearly there is an urgent need for agents that can circumvent resistance when combined with conventional therapies. RRR-α-tocopherol ether-linked acetic acid analog (α-TEA), a small bioactive lipid, exhibits in vitro and in vivo anticancer actions in a variety of cancers, including breast, prostate, and ovarian with little or no effect on normal cells and tissues, which potentially makes it an ideal chemotherapeutic agent. My studies investigated the anticancer actions of α-TEA alone and in combination with therapeutic agents using human breast cancer cell lines. Data show that: (i) Endoplasmic reticulum (ER) stress plays an important role in α-TEA induced apoptosis by enhancing DR5/caspase-8 pro-apoptotic signaling and suppressing anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling, (ii) α-TEA plus tamoxifen act cooperatively to circumvent acquired and de novo tamoxifen resistance, resulting in cancer cell death by apoptosis. Mechanistically, the circumvention of tamoxifen resistance involved induction of DR5/caspase-8 pro-apoptotic mediators and suppression of anti-apoptotic factors c-FLIP and Bcl-2 via ER stress mediated JNK/CHOP/DR5/caspase-8 signaling. (iii) α-TEA alone or with tamoxifen circumvents tamoxifen resistance via disruption of membrane cholesterol rich lipid raft microdomains. Cholesterol blocked the ability of α-TEA + tamoxifen to circumvent tamoxifen resistance. (iv) α-TEA in combination with PI3K, MEK or mTOR inhibitors acted cooperatively to induce apoptosis, by down-regulation of IRS-1/PI3K mediators via JNK. (v) α-TEA plus doxorubicin or cisplatin enhanced apoptosis in p53 mutant human breast cancer cells via targeting p53-inducible genes in a p73-dependent manner; namely, via up-regulation of death receptor-5 (DR5), CD95/APO-1 (Fas), Bax and Noxa, as well as down-regulation of anti-apoptotic mediator Bcl-2. Data showed that p73 responses were downstream of c-Abl, JNK and Yap. (vi) FASN inhibitor alone or with Tamoxifen or α-TEA circumvents tamoxifen resistance, thereby, providing novel strategies for restoring tamoxifen sensitivity to tamoxifen resistant cancers. In summary data show, α-TEA alone and in combination with multiple clinically-relevant anticancer agents is a promising anticancer agent. / text

published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Pathology / Master / Master of Medical Sciences

Objectives: Forkhead box protein P1 (FOXP1) is a transcription factor, and a member of the P-subfamily of forkhead box transcription factor and regulate transcription of a subset of genes that involved in various cellular events. It plays a critical role in regulating cell growth and proliferation, differentiation, embryogenesis, adult tissue homeostasis, and possibly tumorigenesis. Predominant nuclear localisation of FOXP1 protein is commonly expressed at low level in normal tissues and upregulated in proliferative cells. Studies have demonstrated that the loss of FOXP1 expression and cytoplasmic mis-localisation is significantly associated with various malignant cancers, including breast cancer. FOXP1 can act either as a tumor suppressor or as an oncogenic protein in cell-type specific functions. It has been shown to be a co-regulator of estrogen receptor alpha and can modify a specific subset of forkhead box transcription factor class O (FOXO)-target genes. We hypothesise that there is association between FOXP1 expression and patient survival, and explore the potential role of FOXP1 expression as a prognostic marker in breast cancer. Methods: One hundred and twenty breast cancer samples in tissue microarray blocks were examined for FOXP1 expression by immuno-histochemistry. Nuclear and cytoplasmic FOXP1 expression patterns were analysed with clinico-pathological parameters. Statistical analysis was performed using SPSS software to determine the correlation between FOXP1 expression and clinico-pathological parameters. The correlation between subcellular FOXP1 expression and survival was evaluated by COX regression analysis. Results: Nuclear or cytoplasmic FOXP1 expression showed no association with clinico-pathological parameters. However, our results showed that there was significant association with estrogen receptor and progesterone receptor when nuclear and cytoplasmic scores were combined as total FOXP1 score (p=0.022 and p=0.028 respectively). In univariate analysis, high nuclear and cytoplasmic FOXP1 expression had no significant correlation with poor survival, while high total FOXP1 expression was associated with poor overall and disease-specific survival (p=0.045). Tumor stage and lymph-node involvement were significantly related to poorer overall and disease-specific survival, while other clinico-pathological parameters did not. In breast cancer with advanced tumor grade and lymph-node involvement, overall and disease-specific survival are significantly associated with high FOXP1 expression (p=0.041 and p=0.015 respectively). Conclusion: Unlike previous reports, our findings show that increased nuclear and cytoplasmic FOXP1 expression were both observed and high total FOXP1 expression was associated with poorer survival, particularly in cases of advance tumor grade and with lymph node metastases. These finding are supported by a recent report that showed that FOXP1 can up-regulate its own expression by binding to the promoter of FOXP1 and promote cell survival of breast cancer cells by suppressing FOXO-induced apoptosis. It may be possible that FOXP1 expression is up-regulated in a positive feedback loop in breast cancer cells such that there is both increased nuclear transcriptional activity and cytoplasm localisation of FOXP1. Further investigation is necessary to understand the role of FOXP1 in the progression of breast cancer and determine its potential use as a prognostic marker. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Altered histone modifications are known to be observed in cancer cells. Acetylation of histone H4 (acetyl-H4) occurs reversibly on its amino-terminal end at four lysines positions 5, 8, 12 and 16 by Histone Acetyltransferase (HATs). Acetyl-H4 is responsible for a complex set of post-translational modifications that regulate the accessibility of DNA, transcription activation and DNA repair processes. Acetyl-H4 can also acetylate non-histone proteins which eventually control numerous cell signal pathways such as 53BP1, BRCA, AKT. Accumulated evidence showed that P13K, AKT controls the survival signaling pathway and is crucial in developing in drug resistance. This study investigates the global level of all lysine sites of acetyl-H4, its association with p-AKT as well as its prognostic significance in breast cancer. The expression levels of acetyl-H4 were assessed by immunohistochemistry on 102 cases of breast cancer from Queen Mary Hospital in Hong Kong using tissue microarray technology. Nuclear expression of acetyl-H4 was scored and SPSS used for statistical analysis. p-AKT expression data previously obtained in our laboratory (Chen et al.) was also retrieved for correlation with nuclear acetyl-H4 scores. Nuclear acetyl-H4 scores were analyzed for association with a) various clinico-pathological parameters, b) luminal subtypes (ER-and PR-positive), HER-2-positive and triple negative breast cancer, c) p-AKT in breast cancer and d) patient survival by Kaplan-Meier analysis and Cox-regression. By Pearson correlation test, we observed high acetyl-H4 expression was significantly associated with PR-positive breast cancer but not correlated with other clinical parameters and phenotypes of breast cancers (p>0.05). High acetyl-H4 expression was not correlated with p-AKT activity (p=0.84), although it showed inverse correlation with high nuclear p-AKT score. By Kaplan-Meier and Cox-regression analysis, high nuclear acetyl-H4 expression was significantly correlated with poor disease-specific survival in invasive ductal carcinoma (p=0.008 and 0.017 respectively). Multivariate Cox regression analysis confirmed high acetyl-H4 expression (p=0.047) when analyzed together with lymph node involvement (p=0.032) and T-stage (p=0.008) was an independent predictor of poor disease-specific survival in invasive ductal carcinoma. Our results suggest that high acetyl-H4 expression is significantly associated with PR-positive phenotype and lower disease-free survival. The expression of acetyl-H4 was not correlated with p-AKT. Acetyl-H4 may be a potential biomarker to predict poor disease-specific survival for invasive ductal carcinoma. Further investigation is needed for possible use as therapeutic targeting for breast cancer. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Not available / text

Not available / text

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.

No description available.