Browsing by Subject "triple-negative breast cancer"
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Item Clinical Significance of Annexin A2 in Predicting Poor Prognosis in African American Women with Triple-Negative Breast Cancer(2017-05) Gibbs, Lee D.; Vishwanatha, Jamboor K.; Basha, Riyaz; Lovely, Rehana S.; Mathew, Porunelloor A.; Singh, MeharvanTriple-negative breast cancers (TNBC) are identified by the absence of these three major receptors that drive most breast cancer subtypes. TNBC is the most aggressive breast cancer subtype and studies have shown that the incidence of TNBC is much higher in premenopausal African American (AA) women and woman of African descent in comparison to woman of European descent. TNBC in AA women has been associated with worst overall survival after controlling for socioeconomic factors, treatment latency, and tumor receptor expression. This suggests that the clinical outcome of TNBC in AA women may result more from biological differences than access to adequate healthcare. Utilizing a large archived breast cancer cohort of genome sequencing information and the evaluation of these targets in breast tissue and serum can lead to recognition of reliable biological markers that have tremendous potential to enhance detection, treatment, and prognosis. Our previous studies have shown that Annexin A2 (AnxA2), a 36 kda calcium-dependent phospholipid binding protein, is abundantly expressed in TNBC. We have shown AnxA2 to play multiple roles in TNBC by regulating cellular functions; including plasminogen activation, angiogenesis, proliferation, migration, invasion, and metastasis. AnxA2 is one of the most identified proteins expressed in exosomes (small vesicles that are secreted from tumors as metastatic regulators). We have previously demonstrated exosomal AnxA2 contribution to metastasis of TNBC cells in vivo. The proposed study will determine the correlation of AnxA2 with poor prognoses in AA TNBC patients, and establish the clinical significance of exosomal AnxA2 in contributing to the poor clinical outcomes seen in AA TNBC patients. Three specific aims were addressed in this work. Aim 1- Determine the association of secreted exosomal AnxA2 with TNBC amongst AA patients. Aim 2 - Evaluate AnxA2 expression in TNBC tissue samples amongst a breast cancer patient cohort of various breast subtypes. Aim 3 - Determine the correlation of AnxA2 gene expression with poor pathological, prognostic variables and race/ethnicity in TNBC patients through in silico analysis.Item Combination of Small Extracellular Vesicle-Derived Annexin A2 Protein and mRNA as a Potential Predictive Biomarker for Chemotherapy Responsiveness in Aggressive Triple-Negative Breast Cancer(MDPI, 2023-01-09) Desai, Priyanka P.; Narra, Kalyani; James, Johanna D.; Jones, Harlan P.; Tripathi, Amit K.; Vishwanatha, Jamboor K.Small extracellular vesicles (sEVs), mainly exosomes, are nanovesicles that shed from the membrane as intraluminal vesicles of the multivesicular bodies, serve as vehicles that carry cargo influential in modulating the tumor microenvironment for the multi-step process of cancer metastasis. Annexin A2 (AnxA2), a calcium(Ca(2+))-dependent phospholipid-binding protein, is among sEV cargoes. sEV-derived AnxA2 (sEV-AnxA2) protein is involved in the process of metastasis in triple-negative breast cancer (TNBC). The objective of the current study is to determine whether sEV-AnxA2 protein and/or mRNA could be a useful biomarkers to predict the responsiveness of chemotherapy in TNBC. Removal of Immunoglobulin G (IgG) from the serum as well as using the System Bioscience's ExoQuick Ultra kit resulted in efficient sEV isolation and detection of sEV-AnxA2 protein and mRNA compared to the ultracentrifugation method. The standardized method was applied to the twenty TNBC patient sera for sEV isolation. High levels of sEV-AnxA2 protein and/or mRNA were associated with stage 3 and above in TNBC. Four patients who responded to neoadjuvant chemotherapy had high expression of AnxA2 protein and/or mRNA in sEVs, while other four who did not respond to chemotherapy had low levels of AnxA2 protein and mRNA in sEVs. Our data suggest that the sEV-AnxA2 protein and mRNA could be a combined predictive biomarker for responsiveness to chemotherapy in aggressive TNBC.Item Expression and Function of Ligands for Natural Killer Cell Receptors on Triple-negative Breast Cancer Cells(2018-08) Marrufo, Armando M.; Mathew, Porunelloor A.; Mathew, Stephen O.; Jones, Harlan P.; Phillips, Nicole R.Triple-negative breast cancer (TNBC) accounts for 20 percent of all breast cancer cases and is known to be the most invasive form of breast cancer. TNBC's absence of estrogen, progesterone, and human epidermal growth factor-2 receptors makes utilizing hormonal treatments ineffective in suppressing tumor growth. TNBC is associated with poorer prognosis and higher incidences of relapse. Therefore, natural killer cell-mediated immunotherapy shows potential as a treatment option for TNBC. Natural killer cells (NK) are innate lymphoid cells that serves its role in the immune system to eradicate infected and tumor cells. NK cell function is regulated through its receptors interacting with activating and inhibitory ligands on target cells. Lectin-like Transcript-1 (LLT1, CLEC2D) is a ligand that interacts with NKRP1A (CD161) and inhibits NK cell activation. Proliferating Cell Nuclear Antigen (PCNA) is a ligand that interacts with NKp44 and inhibits NK cell activation. We have identified the expression and function of LLT1 and PCNA on TNBC cell lines by flow cytometry, western blot, immunofluorescent microscopy, and chromium-release assay. Our results have demonstrated a higher expression of LLT1 and PCNA on TNBCs than non-tumorigenic breast cell line MCF10A. We have shown that blocking LLT1 interaction with NKRP1A with antibodies and gene knockdown of LLT1, respectively, on TNBCs have increased lysis of TNBCs by primary NK cells. We have also shown that blocking PCNA interaction with NKp44 with antibodies have enhanced killing of TNBCs by NK cells. LLT1 and PCNA expressed on TNBCs sends an inhibitory signal to the NK cell thus serving its role for TNBCs to evade immunosurveillance. Blocking LLT1-NKRP1A or PCNA-NKp44 with antibodies enhances lysis by NK cells and may open a novel immunotherapeutic strategy for patients diagnosed with TNBC.