Browsing by Subject "Breast cancer"
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Item Protein Kinase C-eta Signalling in Breast Cancer(2013-12-01) Pal, Deepanwita; Basu, AlakanandaPal, Deepanwita, Protein kinase C-eta signaling in breast cancer. Doctor of Philosophy (Biochemistry and Molecular Biology), November, 2013, 117 pp, 14 illustrations, 260 References Protein kinase C-eta (PKCη) is a novel member of the PKC family that is important for several cellular processes. PKCη is overexpressed in breast cancer and has been associated with chemotherapeutic resistance. PKCη is the only phorbol ester-sensitive PKC isozyme that resists downregulation upon prolonged treatment with tumorpromoting phorbol esters suggesting its unique regulation. The purpose of this dissertation is to elucidate the mechanism of PKCη regulation and its functional relevance in breast cancer. We have shown that PKCη is upregulated by several structurally and functionally distinct PKC activators in contrast to other PKC isozymes. Activator-induced upregulation of PKCη was associated with its phosphorylation. Our results indicate that novel PKCs are involved in the upregulation of PKCη by PKC activators. We also made a novel observation that PKCη is downregulated via two distinct mechanisms. While inhibition of PKC caused the downregulation of PKCη via proteasome-independent pathway, inhibition of PDK1 led to PKCη downregulation via proteasome-dependent pathway. We further demonstrated that PKCη is important for the growth and survival of breast cancer cells. The unique regulation of PKCη and its implications on breast cancer growth and survival suggests that this pathway could be selectively exploited for targeted therapies for breast cancer.Item ROLE AND REGULATION OF S6 KINASE IN BREAST CANCER(2013-04-12) Sridharan, SavithaPurpose: The 40S ribosomal protein S6 kinase (S6K) acts downstream of the mammalian target of rapamycin (mTOR), which is an important target for cancer therapy. mTOR inhibitors are, however, of limited success, partly due to the activation of the oncogene Akt caused by persistent inhibition of p70 S6 kinase or S6K1 via a negative feedback loop. S6K exists as two homologs, S6K1 and S6K2. While both homologs are overexpressed in breast cancer, little is known about the regulation and functions of S6K2. The objective of the present study is to determine pathways promoting S6K overexpression and whether S6K homologs perform redundant or distinct functions with respect to Akt activation and breast cancer cell survival. Methods: Breast cancer cells were transfected with non-targeting siRNA or siRNA against appropriate proteins and treated with cell death stimuli such as tumor necrosis factor-alpha (TNF), TNF-related apoptosis-inducing ligand (TRAIL), doxorubicin and paclitaxel. Cell death was monitored by staining cells with Annexin V/Yo-pro and propidium iodide. The levels of various proteins were determined by Western blotting. Results: S6K levels correlated with hormone receptor status and signaling through the hormone receptor pathway increased S6K levels. Silencing of S6K1 inhibited whereas knockdown of S6K2 potentiated cell death by various apoptotic stimuli, including TNF and TRAIL. In contrast to S6K1, depletion of S6K2 decreased basal and TNF-induced Akt phosphorylation. Ectopic expression of constitutively-active Akt in MCF-7 cells restored cell survival in S6K2-depleted cells. We have previously shown that activation of Akt induces downregulation of Bid via p53. Knockdown of S6K2 caused an increase in p53 and silencing of Bid blunted the ability of S6K2 deficiency to enhance TNF-induced apoptosis. Conclusions: Our study addresses the mechanism of S6K overexpression and demonstrates for the first time that the two homologs of S6K have distinct effects on Akt activation and cell survival. Thus, targeting S6K2 rather than mTOR may be an effective therapeutic strategy to treat cancers.Item Serum exosomal-annexin A2 is associated with African-American triple-negative breast cancer and promotes angiogenesis(BioMed Central Ltd., 2020-01-28) Chaudhary, Pankaj; Gibbs, Lee D.; Maji, Sayantan; Lewis, Cheryl M.; Suzuki, Sumihiro; Vishwanatha, Jamboor K.BACKGROUND: Limited information is available on biomarker(s) for triple-negative breast cancer (TNBC) that can address the higher incidence and aggressiveness of TNBC in African-American (AA) women. Our previous studies have demonstrated annexin A2 (AnxA2) association with exosomes which promotes angiogenesis and metastasis. Therefore, our goal was to examine the expression and function of exosomal-annexin A2 (exo-AnxA2) derived from the serum samples of breast cancer patients. METHODS: The expression of serum exo-AnxA2 and its association with clinicopathological features of the breast cancer patients were determined. The role of serum exo-AnxA2 to promote angiogenesis was determined by an in vivo Matrigel plug assay. RESULTS: Our results show that the expression of serum exo-AnxA2 in breast cancer patients (n = 169; 83.33 +/- 2.040 ng/mL, P < 0.0001) is high compared to non-cancer females (n = 68; 34.21 +/- 2.238 ng/mL). High expression of exo-AnxA2 levels in breast cancer was significantly associated with tumor grade (P < 0.0001), poor overall survival (hazard ratio (HR) 2.802; 95% confidence intervals (CI) = 1.030-7.620; P = 0.0353), and poor disease-free survival (HR 7.934; 95% CI = 1.778-35.398; P = 0.0301). The expression of serum exo-AnxA2 levels was significantly elevated in TNBC (n = 68; 109.1 +/- 2.905 ng/mL; P < 0.0001) in comparison to ER(+) (n = 50; 57.35 +/- 1.545 ng/mL), HER2(+) (n = 59; 78.25 +/- 1.146 ng/mL), and non-cancer females (n = 68; 34.21 +/- 2.238 ng/mL). Exo-AnxA2 showed diagnostic values with a maximum AUC as 1.000 for TNBC, 0.8304 for ER(+), and 0.9958 for HER2(+) compared to non-cancer females. The expression of serum exo-AnxA2 was significantly elevated in AA women with TNBC (n = 29; 118.9 +/- 4.086 ng/mL, P < 0.0001) in comparison to Caucasian-American TNBC (n = 27; 97.60 +/- 3.298 ng/mL) patients. Our in vivo results suggest a role of serum exo-AnxA2 in angiogenesis and its association with aggressiveness of TNBC in AA women. CONCLUSIONS: Our results demonstrated that the expression of serum exo-AnxA2 is high in AA women with TNBC and promotes angiogenesis. These findings suggest that exo-AnxA2 holds promise as a potential prognosticator of TNBC and may lead to an effective therapeutic option.Item WHAT ARE THE BARRIERS TO BREAST CANCER SCREENING/MAMMOGRAPHY IN FREDERICKSBURG, TX?(2014-03) Baker, Laura; Patel, Pinal; Chiapa-Scifres, Ana; Bowling, JohnBreast cancer screening via mammography has been shown to catch cancer at earlier stages than would otherwise be caught. There are multiple reasons that women do not get mammograms and these reasons tend to differ in rural versus urban populations. This survey was distributed to female patients age 40 and over at Fredericksburg clinic in Fredericksburg, TX. Purpose (a): There are many barriers to breast cancer screening. Research has shown that lack of information about mammography, lower socioeconomic status, lower education level, lack of insurance, and travel burden are barriers to breast cancer screening. A lot of these barriers tend to exist in different proportions in a rural community versus an urban city. These barriers exist in Fredericksburg, but to varying degrees than other areas. The aim of this study was to determine what the barriers to breast cancer screening are in Fredericksburg, TX. Methods (b): Surveys were distributed to female patients over the age of 40 in Fredericksburg Clinic. The study sample included 36 surveys collected from January to March of 2013. The survey included demographic information, medical history, and factors related to breast cancer screening. Results (c): Average age of surveyed patients was 61.4 years. About 70% of respondents said that travel was not a burden to getting an annual mammogram out of the 91.2% that were screened. Out of 77.1% surveyed who thought that travelling was not a burden to getting an annual mammogram, 60% would need to drive less than 20 miles for a mammogram. The relationship between doctor recommendation of a mammogram and insurance coverage was investigated using Pearson product-moment correlation coefficient. There was a positive correlation between the two variables, r=.46, n=36,p=0.005. Conclusions (d): A statistically significant association was found between travel distance and whether they thought travel was a burden. Most patients will travel in order to get a once yearly mammogram but it can be considered to be a burden. Efforts to decrease the distance that some patients have to drive for a mammogram would increase the rates of women that get recommended screenings. Patients that had health insurance were more likely to see a doctor regularly and be recommended further health screenings. With an increase of healthcare coverage, doctors should be able to better recommend preventative health practices to patients.