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Penn State University
1.
Skibinski, Christine G.
preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.
Degree: 2015, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/26720
► As discussed in Chapter 1, Breast cancer is the second leading cause of cancer death in women in the United States, with about 2 million…
(more)
▼ As discussed in Chapter 1, Breast cancer is the second leading cause of cancer death in women in the United States, with about 2 million women at high risk for developing the disease. A current strategy, approved by the FDA, for breast cancer prevention is the daily administration of selective estrogen receptor modulators(SERMS), tamoxifen and raloxifene. These SERMS have proven to be effective at reducing breast cancer incidence in women that are at high risk by 50% and 38%, respectively. However, these agents are poorly accepted as oral chemopreventives even by women at high risk for breast cancer because of concerns of side effects which include thromboembolic events and an increase in endometrial cancers. Furthermore, both agents are ineffective against the more aggressive estrogen receptor negative tumors. A series of experiments have been conducted in our laboratories to test the hypothesis that chemoprevention can be improved by combining SERMS with agents with different mechanisms of action. Such an approach can allow the use of low doses of SERMS and thus reduce their side effects. Literature data provide some support of the protective effects of omega-3 fatty acids against the development of several cancers, including breast cancer. However, the results remain inconsistent which could be due to confounding variables. These confounding variables which have been reported by our group include omega-3:omega-6(n-3:n-6) ratio and caloric intake. A previous study conducted in our laboratories showed that high ratios of omega-3:omega-6 fatty acids(25:1 n-3:n-6) are required to inhibit mammary carcinogenesis in the rat and such high ratios of omega-3:omega-6 fatty acids potentiated the chemopreventive efficacy of tamoxifen.
Studies conducted in Chapter 2 were aimed to test the hypothesis that by using a proteomics approach, novel proteins can be identified that can provide insights into the molecular mechanism by which high ratios of omega-3:omega-6 fatty acids inhibit mammary carcinogenesis. We further hypothesize that proteins identified in a minimally invasive fashion can be used for early detection and to monitor the efficacy of the chemopreventive agents.
We used an isobaric Tagging for Relative and Absolute Quantitation (iTRAQ) method to provide insights into the mechanism, at the protein level, responsible for the chemopreventive action of the high omega-3:omega-6 fatty acid ratios in the absence and presence of tamoxifen in the 1-methyl-1-nitrosourea(MNU)-induced mammary tumor model in the rat; selective proteins were further validated by western blotting. Compared to control (n-3:n-6, 1:1) diet, both 10:1 and 25:1 n-3:n-6 diets upregulated plasma vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1 n-3:n-6, the 25:1 n-3:n-6 plus tamoxifen diet downregulated apolipoprotein E, haptoglobin, and…
Advisors/Committee Members: Karam E El Bayoumy, Dissertation Advisor/Co-Advisor, Arunangshu Das, Committee Member, Thomas E Spratt, Committee Member, Andrea Manni, Committee Member, Mark Kester, Committee Member.
Subjects/Keywords: Docosahexaenoic Acid; Liposome; Breast Cancer Prevention
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APA ·
Chicago ·
MLA ·
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APA (6th Edition):
Skibinski, C. G. (2015). preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/26720
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Skibinski, Christine G. “preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.” 2015. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/26720.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Skibinski, Christine G. “preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.” 2015. Web. 06 Mar 2021.
Vancouver:
Skibinski CG. preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/26720.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Skibinski CG. preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/26720
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
2.
Chin-quee, Karis P.
Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
.
Degree: 2013, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/17496
► ABSTRACT Successful metastasis requires some degree of hospitality from the host organ that is metastasized. In recent years, evidence has been mounting that the primary…
(more)
▼ ABSTRACT
Successful metastasis requires some degree of hospitality from the host organ that is metastasized. In recent years, evidence has been mounting that the primary tumor contributes to adapting this remote organ to increase this hospitality. Interestingly, many in vitro experiments have shown that conditioned media from cancer cells produce physical changes which theoretically could facilitate invasion. These include perturbations in extracellular matrix and of cell to cell adhesions. The conditioned media in these in vitro experiments could be interpreted to be a proxy for either paracrine or endocrine effects, however, when these observations are coupled with evidence from in vivo experiments, it seems possible that primary tumors have remote effects on un-metastasized organs that can elicit changes in them which are pro-metastatic. We have performed a series of experiments designed to characterize and describe changes in osteoblasts (hFOB) which occur as a result of exposure to conditioned medium from breast cancer cells (MDA-MET). Functional experiments aimed at investigating whether these changes are pro-metastatic were included as a means of this characterization. Thus cell to cell adhesions, as well as the ability of the osteoblastic environment to attract MDA-MET cells were both assessed. Further, we investigated mechanistically the bases behind the observations from the functional experiments.
Methods
Confluent hFOB cells were treated with conditioned media from either MDA-MET, MDA-MB-231 HTERT-HME1 or hFOB cells 24 hrs. This treatment conditioned medium was removed, the cells washed and serum-free medium added to the hFOB cells. hFOB-conditioned medium was collected after 18hrs. This medium was then used in in vitro migration assays measuring number of MDA-MET migratory cells by labeling the cells with DNA-binding dye Cyquant; in establishing presence of collagen by western blot; in collagenase assays and in a cytokine array where antibodies to 74 cytokines were embedded on a membrane. The presence of Type 1 collagen receptors was shown by immunocytochemistry. The data were analyzed using one way ANOVA and the Student’s T test.
Results
We found that conditioned medium from hFOB cells that had been treated with MDA-MET-conditioned medium attracted more MDA-MET cells than hFOB cells pre-exposed to its own medium only. We hypothesized that Type 1 collagen fragments of specific length were the chemoattractants responsible for our observed effect. This was evidenced by an increase in collagenase in the conditioned medium of hFOB cells which had been exposed to MDA-MET-conditioned medium. The definitiveness of this evidence was aided by the inherent fidelity of the collagenase enzymes and its Type 1 collagen substrate and the distinctiveness of the product of this enzyme substrate interaction. We also showed that bacterial collagenase, which creates short collagen fragments of non-specific length removed the ability of hFOB -conditioned medium to attract MDA-MET cells. In addition, we showed that at…
Advisors/Committee Members: Henry Joseph Donahue, Dissertation Advisor/Co-Advisor, Henry Joseph Donahue, Committee Chair/Co-Chair, Andrea Manni, Committee Member, Andrea Marie Mastro, Committee Member, David Feith, Committee Member, Lisa M Shantz, Committee Member, Ralph Lauren Keil, Committee Member.
Subjects/Keywords: breast cancer metastasis; pre-metastatic niche; bone; collagen fragments; collagenase
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Chin-quee, K. P. (2013). Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/17496
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Chin-quee, Karis P. “Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
.” 2013. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/17496.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Chin-quee, Karis P. “Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
.” 2013. Web. 06 Mar 2021.
Vancouver:
Chin-quee KP. Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/17496.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Chin-quee KP. Breast cancer cell secretions promote a pre-metastatic niche in bone; an in vitro look
. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/17496
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
3.
Huber-keener, Kathryn Joyce.
Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
.
Degree: 2013, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/15352
► Cancer cells are constantly under stress, a factor which needs to be taken into consideration during the treatment of cancers. Both intrinsic and extrinsic stresses…
(more)
▼ Cancer cells are constantly under stress, a factor which needs to be taken into consideration during the treatment of cancers. Both intrinsic and extrinsic stresses impact the development and progression of neoplasms, down to the level of individual proteins and genes. Stresses like nutrient deficiency, hypoxia, and the immune response are present during normal tumor growth and throughout treatment. Tumor cells that survive these stresses are more adept at surviving hostile conditions and are more resistant to current therapies. Stress, therefore, shapes the tumor cell population. Gene expression alterations are the driving feature behind the adaptive ability of cancer cells to these stresses, and therefore, careful examination of these gene expression changes must be undertaken in order to develop effective therapies.
In the present investigations, we first explore the global alterations of gene expression in tamoxifen resistance. Resistance to tamoxifen (Tam), a widely used antagonist of the estrogen receptor (ER), occurs in one third of patients treated with Tam within 5 years of therapy. A better understanding of gene expression alterations associated with Tam resistance will facilitate circumventing this problem. Using a next generation sequencing approach and a new bioinformatics model, we compared the transcriptomes of Tam-sensitive and Tam-resistant breast cancer cells for identification of genes involved in the development of Tam resistance. We identified differential expression of 1215 mRNA and 513 small RNA transcripts clustered into ERα functions, cell cycle regulation, gen expression, and mitochondrial modification. The extent of alterations found at multiple levels of gene regulation highlights the ability of the Tam-resistant cells to modulate global gene expression. Alterations of small nucleolar RNA, oxidative phosphorylation, and a protein called SIRT3 in Tam-resistant cells present areas for diagnostic and therapeutic tool development for combating resistance to this anti-estrogen agent.
After such a global exploration of cancer cell responses to stress, we next investigated a mechanism of cancer cell survival by exploring the alterations in protein synthesis inhibitor eEF-2K. Studies show that eEF-2K plays a role in cell survival through this inhibition of protein synthesis and that its protein levels are increased in cancer. Post-translational modification of translation machinery is important for its regulation and could be critical for survival of cancer cells encountering stress. Thus, the purpose of our study is to examine the regulation of eEF-2K during stress with a focus on the phosphorylation status and stability of EF-2K protein in cancer cells. Using two human glioma cell lines (T98G and LN229), under stress conditions, we found a paradoxical increase in eEF-2K protein expression with a decrease in eEF-2K protein stability. Phosphorylation may play a role in this altered protein stability as EF-2K has multiple phosphorylation sites that are phosphorylated by the…
Advisors/Committee Members: Jin Ming Yang, Dissertation Advisor/Co-Advisor, Robert G Levenson, Committee Member, Rongling Wu, Committee Member, Willard Freeman, Committee Member, Andrea Manni, Committee Member.
Subjects/Keywords: eEF-2K; tamoxifen; glioma; breast cancer; protein synthesis; next generation-sequencing; protein stability
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Huber-keener, K. J. (2013). Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15352
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Huber-keener, Kathryn Joyce. “Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
.” 2013. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/15352.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Huber-keener, Kathryn Joyce. “Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
.” 2013. Web. 06 Mar 2021.
Vancouver:
Huber-keener KJ. Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/15352.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Huber-keener KJ. Alterations In Gene Expression As A Response
of Tumor Cells To Stresses
. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/15352
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
4.
McCarthy, Sarah Anne.
A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases.
Degree: 2012, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/13790
► There are currently no effective therapeutic treatments to prevent prostate cancer (PCa) bone metastases. Identifying mechanisms that facilitate favorable PCa cell to bone interactions will…
(more)
▼ There are currently no effective therapeutic treatments to prevent prostate cancer (PCa) bone metastases. Identifying mechanisms that facilitate favorable PCa cell to bone interactions will aid in the development of therapies to prevent bone metastases. The objective of this study was to identify a role for calcium and Transient Receptor Potential Vanilloid 6 (TRPV6) ion channels in the metastatic potential and early colonization of osteoblastic PCa cells to murine bone. We proposed that transient increases in serum calcium, following parathyroid hormone (PTH) 1-34 administration, confers a metastatic advantage to PCa cells in circulation, signaled partially via TRPV6 ion channels. To identify the effect of transient elevations in calcium on osteoblastic PCa cell metastatic potential, we employed heterotypic cell adhesion, transwell migration, and invasion assays. Observations from cell adhesion assays suggested that osteoblastic PCa cells increased adhesion to human bone marrow endothelial (hbmE) cells pre-treated with extracellular calcium. Studies suggested that increased extracellular calcium enhanced E-Selectin, VCAM-1 and ICAM-1 cell surface abundance on hbmE cells and that these molecules were partially responsible for increased heterotypic cell adhesion. Increased extracellular calcium also enhanced migration of osteoblastic PCa cell lines, in vitro. To identify the requirement for TRPV6 expression in osteoblastic PCa cell metastatic potential, we reduced TRPV6 expression in osteoblastic PCa cell lines. PCa cells with reduced levels of TRPV6 expression demonstrated slower proliferation rates and an impaired ability to adhere to and invade hbmE cells. Lastly, to identify a role for TRPV6 expression in early PCa cell colonization of murine bone, SCID/Beige mice were administered PTH 1-34 or vehicle, intermittently, then inoculated with PCa cells engineered to express reduced levels of TRPV6. Eight weeks post PCa cell inoculation, PCa cells were identified in long bones of 100% of animals administered PTH 1-34, relative to 20% of animals treated with vehicle. In contrast, PCa cells were identified in only 20% of the long bones of animals administered PTH 1-34, and then inoculated with PCa cells with reduced TRPV6 expression. Our observations support our hypothesis and suggest that calcium and TRPV6 may have a role in facilitating favorable PCa cell to bone interactions.
Advisors/Committee Members: Ronald R Gomes Jr, Dissertation Advisor/Co-Advisor, Henry Joseph Donahue, Committee Member, Patricia Mc Laughlin, Committee Member, Andrea Manni, Committee Member, Andrea Marie Mastro, Committee Member.
Subjects/Keywords: Prostate cancer; TRPV6; parathyroid hormone; osteoblastic; calcium; bone metastases; invasion; adhesion
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
McCarthy, S. A. (2012). A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13790
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
McCarthy, Sarah Anne. “A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases.” 2012. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/13790.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
McCarthy, Sarah Anne. “A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases.” 2012. Web. 06 Mar 2021.
Vancouver:
McCarthy SA. A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/13790.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
McCarthy SA. A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/13790
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
5.
Plichta, Kristin Ann.
Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation.
Degree: 2010, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/11251
► Breast cancers can be divided into subtypes based in part on how closely the tumor cells resemble mammary epithelial cell (MEC) subtypes resident in normal…
(more)
▼ Breast cancers can be divided into subtypes based in part on how closely the tumor cells resemble mammary epithelial cell (MEC) subtypes resident in normal breast tissue. Though breast cancer subtypes differ in their aggressiveness and their response to treatment, the mechanisms by which distinct subtypes arise remain unknown. Traditionally, attempts to explain the varied clinical behavior of breast cancers rely on defining the genetic lesions harbored within individual tumors. However, recent evidence suggests that distinct breast cancer subtypes may arise from distinct MEC lineages, suggesting that some biological features of a given breast cancer subtype may be attributable to its antecedent “cell of origin”.
Elucidating whether MEC lineage impacts the biology of descendant breast cancers presents a formidable challenge. By the time a tumor is clinically detectable, breast cancers have undergone clonal evolution that precludes a reliable retrospective determination of the cell of origin. As such, prospective analyses may be required to determine whether distinct MEC subtypes yield distinct cancer subtypes. We hypothesized that distinct MEC compartments yield different phenotypes in response to an identical oncogenic stimulus. To test this possibility, we generated mouse models that permit doxycycline-dependent expression of transgenes in an MEC compartment-restricted manner and developed strategies to monitor transgene-mediated phenotypes in real-time.
As a first step toward studying malignant transformation of distinct MEC subtypes in mice, we tested experimental strategies designed to permit restriction of transgene expression to distinct MEC compartments in vitro. Transgenic mammary epithelium was partially disaggregated and propagated in 3D culture as mammary organoids, preserving the bilayered arrangement of the basal and luminal MEC compartments. Pairing a tet operator-driven H2B-eGFP reporter transgene with either a basal or luminal MEC transactivator enabled MEC compartment-restricted reporter gene expression. Notably, nuclear fluorescence resulting from H2B-eGFP expression enabled visualization of cellular dynamics within discrete MEC compartments. Through extended, multiparameter live cell imaging of organoids, time-lapse movies were generated that enabled visualization of MEC migration as well as tracking and quantitation of mitotic and apoptotic events.
Next, we adapted this system to co-express the H2B-eGFP reporter together with a tet-operator-regulated oncogenic H-RASG12V allele. Whether expressed in a basal or luminal MEC-restricted manner, H-RASG12V expression reproducibly triggered aberrant organoid growth, reflected in measureable changes in organoid size and shape. Increases in organoid size were attributable to H-RASG12V-mediated increases in cell proliferation and decreases in cell death. In addition, H-RASG12V expression in either MEC compartment drove MECs to both traverse normal compartment boundaries and adopt modes of cellular migration distinct from those encountered in the setting…
Advisors/Committee Members: Edward Joseph Gunther, Dissertation Advisor/Co-Advisor, Edward Joseph Gunther, Committee Chair/Co-Chair, Andrea Manni, Committee Member, Christopher Alan Siedlecki, Committee Member, Lisa M Shantz, Committee Member.
Subjects/Keywords: Ras; mammary organoids; breast cancer; transgenic mice; mammary epithelial cells
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Plichta, K. A. (2010). Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11251
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Plichta, Kristin Ann. “Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation.” 2010. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/11251.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Plichta, Kristin Ann. “Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation.” 2010. Web. 06 Mar 2021.
Vancouver:
Plichta KA. Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation. [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/11251.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Plichta KA. Mammary Epithelial Cell Subtype-Specific Analysis of Ras Pathway Activation. [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11251
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
6.
Yura, Renee E.
MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
.
Degree: 2008, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/8602
► Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in kidney and intestinal epithelial cells. They…
(more)
▼ Meprin metalloproteases, composed of alpha and/or beta subunits, consist of membrane-bound and secreted forms that are abundantly expressed in kidney and intestinal epithelial cells. They are also expressed in the skin and in certain populations of leukocytes. Meprins have been implicated in several inflammatory diseases, such as renal ischemia, diabetic nephropathy, and inflammatory bowel disease, indicating a role for these enzymes in modulation of the immune response. Prior to the initiation of this work, extensive information about the structure and in vitro behavior of the meprins was known, but little was known about their in vivo roles in immune modulation. These studies are the first to demonstrate a relationship between the inflammatory response and the meprins in both systemic and bladder challenge models.
The aim of this work was to determine the role of meprins in the host response to gram-negative uropathic Escherichia coli (E. coli). Initial studies demonstrated marked increases in meprin alpha expression in the urine of women with active urinary tract infections (UTIs), implicating meprin involvement in the host response to bacterial infections. To examine further the role of meprins in the host response to UTI, meprin alpha knockout (alphaKO) and wild-type (WT) mice were challenged with a transurethral inoculation of uropathic E. coli. In this localized model of inflammation, bladder myeloperoxidase (MPO) activity, bladder weight, and bladder permeability were significantly less in alphaKO compared to WT mice after induction of UTI. These data indicate that meprin A is pro-inflammatory, contributing to leukocyte infiltration, edema, and epithelial damage. To determine whether the action of meprin A was the result of a direct interaction with E. coli, extensive in vitro studies were carried out. Meprin A did not decrease the binding of E. coli to bladder cells in culture, nor did it degrade the pili that are responsible for the attachment of E. coli to the bladder epithelium. No evidence of direct interactions between meprin A and E. coli has been found, indicating that the differential response observed in meprin alphaKO mice in comparison to WT is indirect and likely involves the immune system.
A large component of the immune response to E. coli is directed toward lipopolysaccharide (LPS) in the bacterial cell wall. Therefore, the responses of meprin alphaKO, meprin beta knockout (betaKO), meprin alphabeta double knockout (alphabetaKO), and WT mice after intraperitoneal (i.p.) LPS challenge were examined. Genotype-specific differences in response to LPS were observed as early as 1 h after challenge with 2.5 mg/kg i.p. E. coli LPS. Meprin alphaKO mice displayed a decreased systemic response to LPS compared to WT mice and meprin betaKO mice, as indicated by lower blood urea nitrogen (BUN) levels, lower serum TNFalpha levels, and less severe hypothermia, implicating meprin in modulation of the host immune response to endotoxin. These data are consistent with those from UTI studies,…
Advisors/Committee Members: Judith S Bond, Committee Chair/Co-Chair, Sarah Bronson, Committee Member, Robert G Levenson, Committee Member, Andrea Manni, Committee Member, W. Brian Reeves, Committee Member.
Subjects/Keywords: meprins; metalloproteases; lipopolysaccharide; urinary tract infection; transgenic mouse models
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Yura, R. E. (2008). MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8602
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Yura, Renee E. “MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
.” 2008. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/8602.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Yura, Renee E. “MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
.” 2008. Web. 06 Mar 2021.
Vancouver:
Yura RE. MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/8602.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Yura RE. MEPRIN METALLOPROTEASES MODULATE THE HOST RESPONSE TO ESCHERICHIA COLI
. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8602
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University
7.
Rowzee, Anne Marie.
EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
.
Degree: 2008, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/7861
► The ultimate function of the mammary gland is to nourish newborns to sustain mammalian life post-partum. Development and differentiation of the mammary gland occurs postnatally…
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▼ The ultimate function of the mammary gland is to nourish newborns to sustain mammalian life post-partum. Development and differentiation of the mammary gland occurs postnatally under the control of a complex system of hormonal and environmental cues making the mammary gland an important model of study for both developmental biology and endocrinology. Furthermore, breast cancer is the “number one cause of cancer death in Hispanic women” and the “second most common cause of cancer death in white, black, Asian/Pacific Islander and American Indian/Alaska Native women” according to the Centers for Disease Control and Prevention. These statistics make it clear that ongoing research in both breast cancer and normal mammary gland development is imperative to women’s health.
The primary cause of breast cancer is transformation of mammary epithelial cells (MECs) that result in unregulated cell proliferation and subsequent mammary carcinomas. Several components of the insulin-like growth factor (IGF) system, the IGF ligands and the IGF-type I receptor (IGF-1R) in particular, regulate both normal and transformed MEC growth.
Previous studies from our laboratory examined expression of the IGF ligands and the IGF-1R in normal mammary gland development and demonstrated that the IGF ligands and the IGF-1R are expressed in distinct patterns during normal development. Subsequent analysis of receptor affinity for IGF ligands demonstrated that the insulin receptor isoform A (IR-A) is an IGF-II-sensitive signaling receptor and furthermore, that hybrid receptors consisting of equal parts IGF-1R and insulin receptor (IR), preferentially bind IGF ligands.
Herein, we have developed and tested a quantitative PCR assay to accurately measure IGF-1R, IR-A and IR isoform-B (IR-B) expression on the same scale. We have used this assay to quantify mRNA expression of IGF sensitive receptors in primary MECs during mammary gland development. These data demonstrate that IR isoforms are expressed at much higher levels than the IGF-1R at all times. Subsequent protein analysis demonstrated that due to this disproportion, at least 49% of IGF-1R is present as part of a hybrid receptor during pregnancy stages.
We next provide preliminary data that demonstrate preferential activation of the IGF-1R rather than hybrid receptors by IGF-I in vivo. Furthermore, we demonstrate that insulin stimulates IGF-1R activation in vivo, either by stimulating classic IGF-1R or IGF-1R present in a hybrid receptor. The importance of IGF-1R signaling in MEC development is further supported by microarray analysis of a MEC-specific conditional deletion of the IGF-1R during post-pubertal development. These data suggest a functional role for IGF-1R signaling via the PI3K/Akt pathway in regulating expression of cell cycle regulatory molecules. In the final section of this thesis, we present in vitro data that support the findings of the microarray analysis and demonstrate that activation of the PI3K/Akt/mammalian target of rapamycin pathway stimulates cell cycle…
Advisors/Committee Members: Teresa Wood, Committee Chair/Co-Chair, Edward Joseph Gunther, Committee Chair/Co-Chair, Maricarmen Planas Silva, Committee Member, Michael Verderame, Committee Member, Andrea Manni, Committee Member.
Subjects/Keywords: Insulin-like growth factor receptor; Insulin receptor; Mammary epithelial cells; Quantitative PCR; Insulin-like growth factors; Epidermal growth factor
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APA (6th Edition):
Rowzee, A. M. (2008). EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7861
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Rowzee, Anne Marie. “EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
.” 2008. Thesis, Penn State University. Accessed March 06, 2021.
https://submit-etda.libraries.psu.edu/catalog/7861.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Rowzee, Anne Marie. “EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
.” 2008. Web. 06 Mar 2021.
Vancouver:
Rowzee AM. EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 06].
Available from: https://submit-etda.libraries.psu.edu/catalog/7861.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Rowzee AM. EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR
SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH
. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7861
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
.