Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. 14-3-3z-overexpressing tumors exhibited inhibition of apoptosis and increased proliferation. Mechanistically, 14-3-3z decreased p53 expression and retained Akt-phosphorylated FKHRL in the cytosol, inhibiting transcription of pro-apoptotic genes. Additionally, 14-3-3z enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 translation, resulting in increased cell proliferation. Importantly, this 14-3-3z/miR-221/p27/proliferation axis also functions in patients' breast tumors and associates with high-grade cancers. While 14-3-3z has been identified as a crucial player in tumorigenesis, its function in normal mammary gland development remains unknown. Using 14-3-3z conventional knockout mice, we found that loss of 14-3-3z resulted in a significant delay in mammary gland ductal elongation, and decreased branch points, terminal end buds, and proliferation compared to wildtype littermates. In mammary fat pad transplantation assays, 14-3-3z-knockout (14-3-3z-/-) mammary epithelial cells (MECs) had reduced ductal outgrowth and a competitive growth disadvantage compared to wildtype (14-3-3z+/+) MECs. Interestingly, the developmental defects in 14-3-3z-/- mice correlated with a reduction in mammary stem cell (MaSC)-enriched basal population and an increase in the luminal population, indicative of decreased MaSC-self-renewal and increased luminal differentiation. Furthermore, 14-3-3z-/- mammary outgrowths presented aberrant ductal structure and deficiencies in alveogenesis and milk production whereas 14-3-3z+/+ outgrowths retained proper ductal structure and functionality. Together, our findings show that 14-3-3z overexpression plays a causal role in mammary tumorigenesis and progression through deregulation of an integrative signaling network and establishes 14-3-3z as an important player in the homeostatic growth and function of the mammary gland.
","abstract_html":"<p>Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple <em>in vivo</em> and <em>in vitro</em> approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. 14-3-3z-overexpressing tumors exhibited inhibition of apoptosis and increased proliferation. Mechanistically, 14-3-3z decreased p53 expression and retained Akt-phosphorylated FKHRL in the cytosol, inhibiting transcription of pro-apoptotic genes. Additionally, 14-3-3z enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 translation, resulting in increased cell proliferation. Importantly, this 14-3-3z/miR-221/p27/proliferation axis also functions in patients' breast tumors and associates with high-grade cancers. While 14-3-3z has been identified as a crucial player in tumorigenesis, its function in normal mammary gland development remains unknown. Using 14-3-3z conventional knockout mice, we found that loss of 14-3-3z resulted in a significant delay in mammary gland ductal elongation, and decreased branch points, terminal end buds, and proliferation compared to wildtype littermates. In mammary fat pad transplantation assays, 14-3-3z-knockout (14-3-3z-/-) mammary epithelial cells (MECs) had reduced ductal outgrowth and a competitive growth disadvantage compared to wildtype (14-3-3z+/+) MECs. Interestingly, the developmental defects in 14-3-3z-/- mice correlated with a reduction in mammary stem cell (MaSC)-enriched basal population and an increase in the luminal population, indicative of decreased MaSC-self-renewal and increased luminal differentiation. Furthermore, 14-3-3z-/- mammary outgrowths presented aberrant ductal structure and deficiencies in alveogenesis and milk production whereas 14-3-3z+/+ outgrowths retained proper ductal structure and functionality. Together, our findings show that 14-3-3z overexpression plays a causal role in mammary tumorigenesis and progression through deregulation of an integrative signaling network and establishes 14-3-3z as an important player in the homeostatic growth and function of the mammary gland.</p>","abstract_has_math":false,"creators":["Rehman, Sumaiyah"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Dihua Yu, MD, PhD","Varsha Gandhi, PhD","Pierre McCrea, PhD"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-05-01T07:00:00Z","date_published":"2014-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:23Z","subjects":["Breast cancer","mammary development","14-3-3zeta","ywhaz","miR-221","stem cells","cell fate","Biology","Cancer Biology","Developmental Biology","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/456","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Dihua Yu, MD, PhD","Varsha Gandhi, PhD","Pierre McCrea, PhD"]},{"key":"dc:creator","label":"Author","values":["Rehman, Sumaiyah"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2015-05-02T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Breast cancer","mammary development","14-3-3zeta","ywhaz","miR-221","stem cells","cell fate","Biology","Cancer Biology","Developmental Biology","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/456"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. 14-3-3z-overexpressing tumors exhibited inhibition of apoptosis and increased proliferation. Mechanistically, 14-3-3z decreased p53 expression and retained Akt-phosphorylated FKHRL in the cytosol, inhibiting transcription of pro-apoptotic genes. Additionally, 14-3-3z enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 translation, resulting in increased cell proliferation. Importantly, this 14-3-3z/miR-221/p27/proliferation axis also functions in patients' breast tumors and associates with high-grade cancers. While 14-3-3z has been identified as a crucial player in tumorigenesis, its function in normal mammary gland development remains unknown. Using 14-3-3z conventional knockout mice, we found that loss of 14-3-3z resulted in a significant delay in mammary gland ductal elongation, and decreased branch points, terminal end buds, and proliferation compared to wildtype littermates. In mammary fat pad transplantation assays, 14-3-3z-knockout (14-3-3z-/-) mammary epithelial cells (MECs) had reduced ductal outgrowth and a competitive growth disadvantage compared to wildtype (14-3-3z+/+) MECs. Interestingly, the developmental defects in 14-3-3z-/- mice correlated with a reduction in mammary stem cell (MaSC)-enriched basal population and an increase in the luminal population, indicative of decreased MaSC-self-renewal and increased luminal differentiation. Furthermore, 14-3-3z-/- mammary outgrowths presented aberrant ductal structure and deficiencies in alveogenesis and milk production whereas 14-3-3z+/+ outgrowths retained proper ductal structure and functionality. Together, our findings show that 14-3-3z overexpression plays a causal role in mammary tumorigenesis and progression through deregulation of an integrative signaling network and establishes 14-3-3z as an important player in the homeostatic growth and function of the mammary gland.
"]},{"key":"dc:title","label":"Title","values":["Regulation of Mammary Gland Development and Tumorigenesis By 14-3-3 Zeta"]}]}],"canonical_facts":{"dc:contributor":["Dihua Yu, MD, PhD","Varsha Gandhi, PhD","Pierre McCrea, PhD"],"dc:creator":["Rehman, Sumaiyah"],"dc:date.available":["2015-05-02T07:00:00Z"],"dc:description.abstract":["Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple in vivo and in vitro approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. 14-3-3z-overexpressing tumors exhibited inhibition of apoptosis and increased proliferation. Mechanistically, 14-3-3z decreased p53 expression and retained Akt-phosphorylated FKHRL in the cytosol, inhibiting transcription of pro-apoptotic genes. Additionally, 14-3-3z enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 translation, resulting in increased cell proliferation. Importantly, this 14-3-3z/miR-221/p27/proliferation axis also functions in patients' breast tumors and associates with high-grade cancers. While 14-3-3z has been identified as a crucial player in tumorigenesis, its function in normal mammary gland development remains unknown. Using 14-3-3z conventional knockout mice, we found that loss of 14-3-3z resulted in a significant delay in mammary gland ductal elongation, and decreased branch points, terminal end buds, and proliferation compared to wildtype littermates. In mammary fat pad transplantation assays, 14-3-3z-knockout (14-3-3z-/-) mammary epithelial cells (MECs) had reduced ductal outgrowth and a competitive growth disadvantage compared to wildtype (14-3-3z+/+) MECs. Interestingly, the developmental defects in 14-3-3z-/- mice correlated with a reduction in mammary stem cell (MaSC)-enriched basal population and an increase in the luminal population, indicative of decreased MaSC-self-renewal and increased luminal differentiation. Furthermore, 14-3-3z-/- mammary outgrowths presented aberrant ductal structure and deficiencies in alveogenesis and milk production whereas 14-3-3z+/+ outgrowths retained proper ductal structure and functionality. Together, our findings show that 14-3-3z overexpression plays a causal role in mammary tumorigenesis and progression through deregulation of an integrative signaling network and establishes 14-3-3z as an important player in the homeostatic growth and function of the mammary gland.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/456"],"dc:subject":["Breast cancer","mammary development","14-3-3zeta","ywhaz","miR-221","stem cells","cell fate","Biology","Cancer Biology","Developmental Biology","Medicine and Health Sciences"],"dc:title":["Regulation of Mammary Gland Development and Tumorigenesis By 14-3-3 Zeta"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:23Z"}