The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C encoding the truncated PDGF C protein (t-PDGF C). Specific aims of this dissertation are to determine the role of full-length PDGF C (FL-PDGF C) and t-PDGF C in breast cancer and to characterize their subcellular localizations. This study found that although t-PDGF C presumably lacks the signal peptide, it is secreted as a heterodimer with FL-PDGF C which can undergo extracellular proteolytic activation. Furthermore, PDGF C was found in the nuclear fraction of breast cancer cells, suggesting an uncharacterized function in breast cancer. A putative nuclear localization sequence in PDGF C showed little effect on its nuclear localization as determined by the point mutagenesis assay. Interestingly, we found that the serine protease cleavage site in the hinge region plays a critical role for both extracellular proteolytic processing and nuclear accumulation of PDGF C, suggesting that the biochemical processing and the subcellular localization are co-regulated. For the functional study, we established in vitro cell models engineered to overexpress PDGF C isoforms or inhibit its expression. This study found that PDGF C expression correlates with cell proliferation, invasive phenotype and anchorage-independent growth in vitro. Importantly, t-PDGF C expression further promoted PDGF C-induced phenotypic transformation. PDGF C downregulation decreased tumor growth and metastatic potential in vivo. Taken together, this study identified PDGF C and its splice variant as key signaling molecules in breast cancer. In addition, once thought of as primarily an extracellular signaling molecule, nuclear localization marks a potentially important paradigm shift in PDGF C biology.
","abstract_html":"<p>The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C encoding the truncated PDGF C protein (t-PDGF C). Specific aims of this dissertation are to determine the role of full-length PDGF C (FL-PDGF C) and t-PDGF C in breast cancer and to characterize their subcellular localizations. This study found that although t-PDGF C presumably lacks the signal peptide, it is secreted as a heterodimer with FL-PDGF C which can undergo extracellular proteolytic activation. Furthermore, PDGF C was found in the nuclear fraction of breast cancer cells, suggesting an uncharacterized function in breast cancer. A putative nuclear localization sequence in PDGF C showed little effect on its nuclear localization as determined by the point mutagenesis assay. Interestingly, we found that the serine protease cleavage site in the hinge region plays a critical role for both extracellular proteolytic processing and nuclear accumulation of PDGF C, suggesting that the biochemical processing and the subcellular localization are co-regulated. For the functional study, we established in vitro cell models engineered to overexpress PDGF C isoforms or inhibit its expression. This study found that PDGF C expression correlates with cell proliferation, invasive phenotype and anchorage-independent growth in vitro. Importantly, t-PDGF C expression further promoted PDGF C-induced phenotypic transformation. PDGF C downregulation decreased tumor growth and metastatic potential in vivo. Taken together, this study identified PDGF C and its splice variant as key signaling molecules in breast cancer. In addition, once thought of as primarily an extracellular signaling molecule, nuclear localization marks a potentially important paradigm shift in PDGF C biology.</p>","abstract_has_math":false,"creators":["Bottrell, Alyssa"],"institution":null,"degree_name":"Ph.D.","degree_level":"Open Access Dissertation","degree_discipline":"Pathology","degree_department":null,"school":null,"contributors":["Hyeong-Reh C. Kim"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-01-01T08:00:00Z","date_published":"2014-01-01T08:00:00Z","updated_at":"2026-07-24T06:00:09Z","subjects":["Pathology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.wayne.edu/oa_dissertations/1285","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Hyeong-Reh C. Kim"]},{"key":"dc:creator","label":"Author","values":["Bottrell, Alyssa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2014-01-01T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Pathology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Open Access Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pathology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.wayne.edu/oa_dissertations/1285"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C encoding the truncated PDGF C protein (t-PDGF C). Specific aims of this dissertation are to determine the role of full-length PDGF C (FL-PDGF C) and t-PDGF C in breast cancer and to characterize their subcellular localizations. This study found that although t-PDGF C presumably lacks the signal peptide, it is secreted as a heterodimer with FL-PDGF C which can undergo extracellular proteolytic activation. Furthermore, PDGF C was found in the nuclear fraction of breast cancer cells, suggesting an uncharacterized function in breast cancer. A putative nuclear localization sequence in PDGF C showed little effect on its nuclear localization as determined by the point mutagenesis assay. Interestingly, we found that the serine protease cleavage site in the hinge region plays a critical role for both extracellular proteolytic processing and nuclear accumulation of PDGF C, suggesting that the biochemical processing and the subcellular localization are co-regulated. For the functional study, we established in vitro cell models engineered to overexpress PDGF C isoforms or inhibit its expression. This study found that PDGF C expression correlates with cell proliferation, invasive phenotype and anchorage-independent growth in vitro. Importantly, t-PDGF C expression further promoted PDGF C-induced phenotypic transformation. PDGF C downregulation decreased tumor growth and metastatic potential in vivo. Taken together, this study identified PDGF C and its splice variant as key signaling molecules in breast cancer. In addition, once thought of as primarily an extracellular signaling molecule, nuclear localization marks a potentially important paradigm shift in PDGF C biology.
"]},{"key":"dc:title","label":"Title","values":["The Role Of Pdgf C And Its Splice Variant In Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Hyeong-Reh C. Kim"],"dc:creator":["Bottrell, Alyssa"],"dc:date.available":["2014-01-01T08:00:00Z"],"dc:description.abstract":["The PDGF family consists of four members; while PDGF A and B are secreted as active dimers, PDGF C and D are secreted as latent dimers that undergo serine protease-mediated extracellular proteolytic activation. Gene expression analysis of breast cancer cell lines showed that PDGF C expression is associated with Basal B subtype breast cancer cells which have cancer stem cell-like characteristics. Furthermore, PDGF C expression is associated with triple-negative (estrogen receptor-, progesterone receptor- and HER2/neu-negative) breast cancer cells, a challenging type of breast cancer to treat. During the course of our study, we discovered a splice variant of PDGF C encoding the truncated PDGF C protein (t-PDGF C). Specific aims of this dissertation are to determine the role of full-length PDGF C (FL-PDGF C) and t-PDGF C in breast cancer and to characterize their subcellular localizations. This study found that although t-PDGF C presumably lacks the signal peptide, it is secreted as a heterodimer with FL-PDGF C which can undergo extracellular proteolytic activation. Furthermore, PDGF C was found in the nuclear fraction of breast cancer cells, suggesting an uncharacterized function in breast cancer. A putative nuclear localization sequence in PDGF C showed little effect on its nuclear localization as determined by the point mutagenesis assay. Interestingly, we found that the serine protease cleavage site in the hinge region plays a critical role for both extracellular proteolytic processing and nuclear accumulation of PDGF C, suggesting that the biochemical processing and the subcellular localization are co-regulated. For the functional study, we established in vitro cell models engineered to overexpress PDGF C isoforms or inhibit its expression. This study found that PDGF C expression correlates with cell proliferation, invasive phenotype and anchorage-independent growth in vitro. Importantly, t-PDGF C expression further promoted PDGF C-induced phenotypic transformation. PDGF C downregulation decreased tumor growth and metastatic potential in vivo. Taken together, this study identified PDGF C and its splice variant as key signaling molecules in breast cancer. In addition, once thought of as primarily an extracellular signaling molecule, nuclear localization marks a potentially important paradigm shift in PDGF C biology.
"],"dc:identifier":["https://digitalcommons.wayne.edu/oa_dissertations/1285"],"dc:subject":["Pathology"],"dc:title":["The Role Of Pdgf C And Its Splice Variant In Breast Cancer"],"thesis:degree_discipline":["Pathology"],"thesis:degree_level":["Open Access Dissertation"],"thesis:degree_name":["Ph.D."]},"updated_at":"2026-07-24T06:00:09Z"}