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- All Subjects: Breast Cancer
- Creators: Chang, Yung
Description
Cancer is a disease that affects millions of people worldwide each year. The metastatic progression of cancer is the number one reason for cancer related deaths. Cancer preventions rely on the early identification of tumor cells as well as a detailed understanding of cancer as a whole. Identifying proteins specific to tumor cells provide an opportunity to develop noninvasive clinical tests and further our understanding of tumor biology. Using liquid chromatography-mass spectrometry (LC-MS/MS) a short peptide was identified in pancreatic cancer patient plasma that was not found in normal samples, and mapped back to QSOX1 protein. Immunohistochemistry was performed probing for QSOX1 in tumor tissue and discovered that QSOX1 is highly over-expressed in pancreatic and breast tumors. QSOX1 is a FAD-dependent sulfhydryl oxidase that is extremely efficient at forming disulfide bonds in nascent proteins. While the enzymology of QSOX1 has been well studied, the tumor biology of QSOX1 has not been studied. To begin to determine the advantage that QSOX1 over-expression provides to tumors, short hairpin RNA (shRNA) were used to reduce the expression of QSOX1 in human tumor cell lines. Following the loss of QSOX1 growth rate, apoptosis, cell cycle and invasive potential were compared between tumor cells transduced with shQSOX1 and control tumor cells. Knock-down of QSOX1 protein suppressed tumor cell growth but had no effect on apoptosis and cell cycle regulation. However, shQSOX1 dramatically inhibited the abilities of both pancreatic and breast tumor cells to invade through Matrigel in a modified Boyden chamber assay. Mechanistically, shQSOX1-transduced tumor cells secreted MMP-2 and -9 that were less active than MMP-2 and -9 from control cells. Taken together, these results suggest that the mechanism of QSOX1-mediated tumor cell invasion is through the post-translational activation of MMPs. This dissertation represents the first in depth study of the role that QSOX1 plays in tumor cell biology.
ContributorsKatchman, Benjamin A (Author) / Lake, Douglas F. (Thesis advisor) / Rawls, Jeffery A (Committee member) / Miller, Laurence J (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2012
Description
Breast cancer is the most common cancer and currently the second leading cause of death among women in the United States. Patients’ five-year relative survival rate decreases from 99% to 25% when breast cancer is diagnosed late. Immune checkpoint blockage has shown to be a promising therapy to improve patients’ outcome in many other cancers. However, due to the lack of early diagnosis, the treatment is normally given in the later stages. An early diagnosis system for breast cancer could potentially revolutionize current treatment strategies, improve patients’ outcomes and even eradicate the disease. The current breast cancer diagnostic methods cannot meet this demand. A simple, effective, noninvasive and inexpensive early diagnostic technology is needed. Immunosignature technology leverages the power of the immune system to find cancer early. Antibodies targeting tumor antigens in the blood are probed on a high-throughput random peptide array and generate a specific binding pattern called the immunosignature.
In this dissertation, I propose a scenario for using immunosignature technology to detect breast cancer early and to implement an early treatment strategy by using the PD-L1 immune checkpoint inhibitor. I develop a methodology to describe the early diagnosis and treatment of breast cancer in a FVB/N neuN breast cancer mouse model. By comparing FVB/N neuN transgenic mice and age-matched wild type controls, I have found and validated specific immunosignatures at multiple time points before tumors are palpable. Immunosignatures change along with tumor development. Using a late-stage immunosignature to predict early samples, or vice versa, cannot achieve high prediction performance. By using the immunosignature of early breast cancer, I show that at the time of diagnosis, early treatment with the checkpoint blockade, anti-PD-L1, inhibits tumor growth in FVB/N neuN transgenic mouse model. The mRNA analysis of the PD-L1 level in mice mammary glands suggests that it is more effective to have treatment early.
Novel discoveries are changing understanding of breast cancer and improving strategies in clinical treatment. Researchers and healthcare professionals are actively working in the early diagnosis and early treatment fields. This dissertation provides a step along the road for better diagnosis and treatment of breast cancer.
In this dissertation, I propose a scenario for using immunosignature technology to detect breast cancer early and to implement an early treatment strategy by using the PD-L1 immune checkpoint inhibitor. I develop a methodology to describe the early diagnosis and treatment of breast cancer in a FVB/N neuN breast cancer mouse model. By comparing FVB/N neuN transgenic mice and age-matched wild type controls, I have found and validated specific immunosignatures at multiple time points before tumors are palpable. Immunosignatures change along with tumor development. Using a late-stage immunosignature to predict early samples, or vice versa, cannot achieve high prediction performance. By using the immunosignature of early breast cancer, I show that at the time of diagnosis, early treatment with the checkpoint blockade, anti-PD-L1, inhibits tumor growth in FVB/N neuN transgenic mouse model. The mRNA analysis of the PD-L1 level in mice mammary glands suggests that it is more effective to have treatment early.
Novel discoveries are changing understanding of breast cancer and improving strategies in clinical treatment. Researchers and healthcare professionals are actively working in the early diagnosis and early treatment fields. This dissertation provides a step along the road for better diagnosis and treatment of breast cancer.
ContributorsDuan, Hu (Author) / Johnston, Stephen Albert (Thesis advisor) / Hartwell, Leland Harrison (Committee member) / Dinu, Valentin (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2015
Description
Stromal cells play an important role in facilitating disease progression of ductal carcinoma. Cancer associated fibroblasts (CAFs) are an important component of the extracellular matrix (ECM) which constitutes the microenvironment of breast tumor cells. They are known to participate in chemotherapeutic drug resistance by modulating various biochemical and biophysical factors that contribute to increased matrix stiffness and collagen I density of the tumor-adjacent stroma. To address these issues in terms of patient treatment, anti-cancer drug regimes have been assembled to incorporate both chemotherapeutic as well as anti-fibrotic drugs to both target tumor cells while also diminishing the elastic modulus of the microenvironment by targeting CAFs. The quantitative assessment of these drug regimes on tumor progression is missing in terms of CAFs role alone.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
A high density 3D tumor model was utilized to recapitulate the tumor microenvironment of ductal carcinoma in vitro. The tumor model consisted of MDA-MB-231 tumors seeded within micromolded collagen wells, chemically immobilized upon a surface treated PDMS substrate. CAFs were seeded within the greater collagen structure from which the microwells were formed. The combinatorial effect of anti-fibrotic drug (Tranilast) and chemotherapy drug (Doxorubicin) were studied within 3D co culture conditions. Specifically, the combinatorial effects of the drugs on tumor cell viability, proliferation, and invasion were examined dynamically upon coculture with CAFs using the microengineered model.
The results of the study showed that the combinatorial effects of Tranilast and Doxorubicin significantly decreased the proliferative ability of tumor cells, in addition to significantly decreasing the ability of tumor cells to remain viable and invade their surrounding stroma, compared to control conditions.
ContributorsSilva, Casey Rudolph (Author) / Nikkhah, Mehdi (Thesis director) / Saini, Harpinder (Committee member) / Harrington Bioengineering Program (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05