+publisher:"Penn State University" +contributor:("Edward Joseph Gunther, Dissertation Advisor/Co-Advisor")

You searched for +publisher:"Penn State University" +contributor:("Edward Joseph Gunther, Dissertation Advisor/Co-Advisor"). Showing records 1 – 4 of 4 total matches.

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Penn State University

1. Cleary, Allison Shea. Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions.

Degree: 2014, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/22628

► Breast cancer is a heterogeneous disease on two levels. First, breast cancers display inter-tumor heterogeneity evidenced by the diversity of clinically and molecularly defined tumor… (more)

▼ Breast cancer is a heterogeneous disease on two levels. First, breast cancers display inter-tumor heterogeneity evidenced by the diversity of clinically and molecularly defined tumor subtypes that differ with respect to disease progression and drug sensitivity. Second, individual breast cancers display remarkable intra-tumor heterogeneity evidenced by the diversity of component tumor cell subtypes co-residing within each cancer that differ with respect to cell morphology, proliferation rate, metastatic potential, drug sensitivity, and capacity for tumor reconstitution. The cellular mechanisms that generate and maintain breast cancer heterogeneity, both at the level of tumor subtype and tumor cell subtype, remain poorly understood. Using mouse models of human breast cancer, this dissertation examines whether and how breast cancer heterogeneity derives from the diverse and highly interactive cell subtypes that comprise the normal mammary gland, breast cancer’s tissue-of-origin. In one set of experiments directed at uncovering the origin of tumor subtypes, we examined why transgenic mouse models of breast cancer nearly always yield a hormone receptor (HR)-negative mammary cancer subtype. In the mammary gland, mature ducts consist of basal and luminal mammary epithelial cell (MEC) subtypes. The luminal epithelial compartment can be further subdivided into hormone receptor (HR)-positive and HR-negative subsets. While human breast cancers frequently express HRs and depend on ovarian hormones for growth, transgenic mouse models of breast cancers show an unexplained bias toward HR-negative disease. Since the majority of mouse breast cancer models use the mouse mammary tumor virus long terminal repeat (MMTV-LTR) as a mammary-specific promoter element, we examined whether MMTV targets transgene expression to a specific MEC compartment. Using the MMTV-LTR to drive expression of a nuclear H2BGFP reporter transgene, we observed nuclear labeling restricted to HR-negative cells within the luminal compartment. Combining this labeling strategy with MMTV-directed expression of the Neu oncogene, we found Neu transgene expression was similarly enriched within HR-negative luminal MECs. Further, Neu-initiated neoplasias were comprised entirely of HR-negative cells from the carcinoma-in-situ stage onward. Thus, MMTV-driven Neu expression targets HR-negative luminal cells, culminating in HR-negative tumors. We propose that the HR-negative phenotype of many mouse breast cancer models can be explained by MMTV-driven transgene expression in HR-negative MECs. In another set of experiments, we sought to study interactions between tumor cell subtypes. To do this, we developed a novel experimental platform for culturing chimeric mammary organoids which permits analysis of both the cell-autonomous and non-autonomous effects of oncogene expression. By combining primary MECs from two different transgenic donors, chimeric mammary organoids were assembled consisting of intermingled populations of genetically distinct donor MECs that could each be… Advisors/Committee Members: Advisor%22%29&pagesize-30">Edward Joseph Gunther, Dissertation Advisor/Co-Advisor, Edward Joseph Gunther, Committee Chair/Co-Chair, David Feith, Committee Member, Leslie Joan Parent, Committee Member, Todd Schell, Committee Member, Raghu Sinha, Committee Member.

Subjects/Keywords: tumor heterogeneity; interclonal cooperation; breast cancer; mammary gland; transgenic mice; 3D organoid culture; FACS

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APA (6^th Edition):

Cleary, A. S. (2014). Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/22628

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Cleary, Allison Shea. “Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions.” 2014. Thesis, Penn State University. Accessed March 06, 2021. https://submit-etda.libraries.psu.edu/catalog/22628.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Cleary, Allison Shea. “Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions.” 2014. Web. 06 Mar 2021.

Vancouver:

Cleary AS. Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions. [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Mar 06]. Available from: https://submit-etda.libraries.psu.edu/catalog/22628.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Cleary AS. Heterogeneity in Mammary Cancer: Using Mouse Models to Investigate Tumor Subtype Origins and Interclonal Interactions. [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/22628

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. Mathers, Jessica. TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12179

► With as many as 1 in 8 women diagnosed with breast cancer in their lifetime, breast cancer is the most commonly diagnosed cancer in women… (more)

▼ With as many as 1 in 8 women diagnosed with breast cancer in their lifetime, breast cancer is the most commonly diagnosed cancer in women in the Western Hemisphere and the second most common cause of cancer-related death in females. Decades of study have uncovered causative exposures and mutations that transform normal mammary epithelial cells (MECs) into breast cancer cells. Nonetheless, the cellular mechanisms that define the clinical behavior of breast cancers remain incompletely defined. Lineage commitment pathways yield diverse MEC cell types within the breast, and recent findings suggest these MEC lineage hierarchies may persist within breast cancers, perhaps helping to explain the cellular heterogeneity seen in tumors. To extend these studies, models are needed that permit cell fate tracking in the discrete MEC compartments of both normal and malignant mammary tissue. In this work, we describe novel transgenic mouse models that permit temporally-regulated, MEC compartment-restricted expression of a histone-fused eGFP (H2B-eGFP) reporter in both normal and malignant mammary epithelium. Transactivator transgenes expressed in either the luminal or basal layer of mammary ducts drove widespread H2B-eGFP labeling of luminal or basal MECs, respectively. We tested whether the H2B-eGFP reporter could be used to track cell divisions within labeled MEC compartments. Indeed, when H2B-eGFP transgene expression was switched off in pulse-chase experiments, washout of label depended on partitioning of labeled histones between daughter cells during MEC proliferation. Moreover, the H2B-eGFP nuclear label was readily detectable in live MECs, enabling live cell imaging of MECs propagated in culture. H2B-eGFP labeling was used for short-term lineage tracing of MECs during lobuloalveolar development. Hormones of pregnancy trigger the development of bi-layered alveolar outgrowths that are believed to arise from luminal progenitor cells. Contrasting with this model, we found that labeled cells from both the luminal and basal MEC compartments contribute to alveolar outgrowths. Furthermore, both luminal and basal MECs proliferated while contributing to alveologenesis, and did not merely migrate into alveoli or become incorporated as “bystanders”. These findings clarify a lineage commitment pathway operative during a key, hormonally-driven stage of mammary gland development. In separate studies, we labeled either basal or luminal MECs residing in the secretory epithelium of lactating mice to examine whether a subset of these MECs persist throughout the mammary gland remodeling program triggered by weaning. Remarkably, substantial numbers of both luminal and basal MECs survived mammary gland involution and contributed to remodeled ducts. These findings have implications for understanding how a lactation-involution cycle protects against breast cancer in rodents and humans. In other studies, the H2B-eGFP labeling strategy was applied in the context of Wnt1-driven transgenic mouse models of breast cancer. Here, we sought to use pulse-chase… Advisors/Committee Members: Advisor%22%29&pagesize-30">Edward Joseph Gunther, Dissertation Advisor/Co-Advisor, Edward Joseph Gunther, Committee Chair/Co-Chair, Sarah Bronson, Committee Member, Gary Alan Clawson, Committee Member, Jiyue Zhu, Committee Member.

Subjects/Keywords: mammary stem cell; breast cancer; mammary gland

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Mathers, J. (2011). TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12179

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Mathers, Jessica. “TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE .” 2011. Thesis, Penn State University. Accessed March 06, 2021. https://submit-etda.libraries.psu.edu/catalog/12179.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Mathers, Jessica. “TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE .” 2011. Web. 06 Mar 2021.

Vancouver:

Mathers J. TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 06]. Available from: https://submit-etda.libraries.psu.edu/catalog/12179.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Mathers J. TRACKING MAMMARY EPITHELIAL CELL LINEAGE AND CELL DIVISIONS IN THE NORMAL MAMMARY GLAND AND MAMMARY NEOPLASIA USING TRANSGENIC MICE . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12179

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Keller, Ross Richard. Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations.

Degree: 2018, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/15024rrk145

► Cancer is a disease of evolution. Species evolve because mutations are passed to progeny through the germline, but somatic cells acquire mutations as well, and… (more)

▼ Cancer is a disease of evolution. Species evolve because mutations are passed to progeny through the germline, but somatic cells acquire mutations as well, and somatic mutation can initiate cancer. In addition, established cancers themselves evolve. Within a tumor, ongoing mutagenesis creates cell-to-cell genetic diversity, allowing subpopulations to undergo natural selection in Darwinian fashion. With a surplus of cells and a staggering number of potential mutations, evolution could, in theory, empower a tumor to overcome a plethora of obstacles. But fortunately, cancer evolution is restricted. Chemical, genetic, cellular, and environmental evolutionary constraints make cancer vulnerable. To uncover novel constraints, we utilized mouse model systems of breast cancer, specifically models driven by mutations in the adenomatous polyposis coli (Apc) gene, which antagonizes oncogenic Wnt signaling. In Chapter 2, we show that chemical and genetic constraints can direct which oncogenes are selected to cooperate in driving cancer. In mice that develop reversible, Wnt pathway-dependent mammary cancers (iWnt mice), exposure to chemical carcinogens that preferentially form adducts with either adenine (7,12 dimethylbenz(a)anthracene, DMBA) or thymine (N-ethyl-N-nitrosourea, ENU) resulted in activating mutations affecting different genes in the oncogenic Ras-Raf pathway (HrasCAA61CTA or BrafGTG636GAG, respectively). Both these mutations occur at A:T base pairs, but differ because in Hras, adenine resides on the sense strand, while in Braf, thymine does. This implicated strand-biased processes, such as strand-specific DNA repair, in mutagenesis. To confirm this, we generated DMBA- and ENU-induced mammary tumors in Apcmin mice, which inherit one nonfunctional Apc allele but routinely acquire second-hit mutations en route to mammary tumorigenesis. Exposure to each chemical led to distinct second-hit Apc mutation patterns, including strand-inverse mutation signatures at A:T sites, which precisely matched the mutation bias observed in Ras-Raf oncogenes. The findings indicate that a mutagen’s chemistry paired with DNA repair processes may have an outsized influence on which cancer driver genes are selected, independent of other pressures. In Chapter 3, we exploited patterns of second-hit Apc driver mutations to demonstrate that ionizing radiation (IR) perturbs mutation spectra in a dose-dependent manner, implying different doses drive cancer evolution via different mechanisms. In Apcmin mice, low-dose IR exposure (1 Gy), whether administered as a one-time dose or fractionated daily doses increased mammary tumor incidence without altering the mutation spectrum compared with IR-naïve tumors. By contrast, high-dose IR (5 Gy) not only increased tumor incidence, but also shifted the mutation spectrum towards microdeletions, a putative signature of DNA double strand break (DSB) repair. Since IR is routinely used to treat breast cancer patients, we went on to determine how IR exposures impact mammary tumor cells. We introduced the Apcmin… Advisors/Committee Members: Advisor%22%29&pagesize-30">Edward Joseph Gunther, Dissertation Advisor/Co-Advisor, Edward Joseph Gunther, Committee Chair/Co-Chair, Kristin Ann Eckert, Committee Member, Lisa M Shantz, Committee Member, James Riley Broach, Outside Member, Sarah Bronson, Committee Member.

Subjects/Keywords: Cancer; Evolution; Genetics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Keller, R. R. (2018). Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15024rrk145

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Keller, Ross Richard. “Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations.” 2018. Thesis, Penn State University. Accessed March 06, 2021. https://submit-etda.libraries.psu.edu/catalog/15024rrk145.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Keller, Ross Richard. “Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations.” 2018. Web. 06 Mar 2021.

Vancouver:

Keller RR. Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations. [Internet] [Thesis]. Penn State University; 2018. [cited 2021 Mar 06]. Available from: https://submit-etda.libraries.psu.edu/catalog/15024rrk145.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Keller RR. Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations. [Thesis]. Penn State University; 2018. Available from: https://submit-etda.libraries.psu.edu/catalog/15024rrk145

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. 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: Advisor%22%29&pagesize-30">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 (6^th 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 (16^th 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 (7^th 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

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