Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that
mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in
breast cancer generates two low molecular weight (LMW) isoforms that exhibit both
enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress
LMW-E and associate with poor survival. Therefore, we hypothesize that LMW-E
disrupts normal mammary acinar morphogenesis and serves as the initial route into
breast tumor development. We first demonstrate that LMW-E overexpression in
non-tumorigenic hMECs is sufficient to induce tumor formation in athymic mice
significantly more than overexpression of full-length cyclin E and requires CDK2-
associated kinase activity. Further in vivo passaging of these tumors augments
LMW-E expression and tumorigenic potential. When subjected to acinar
morphogenesis in vitro, LMW-E mediates significant morphological disruption by
generating hyperproliferative and multi-acinar complexes. Proteomic analysis of
patient tissues and tumor cells with high LMW-E expression reveals that the
activation of the b-Raf-ERK1/2-mTOR pathway in concert with high LMW-E
expression predicts poor patient survival. Combination treatment using roscovitine
(CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (b-raf inhibitor)
effectively prevented aberrant acinar formation in LMW-E-expressing cells by
inducing the G1/S cell cycle arrest. In addition, the LMW-E-expressing tumor cells
exhibit phenotypes characteristic of the EMT and enhanced cellular invasiveness.
These tumor cells also enrich for cells with CSC phenotypes such as increased
CD44hi/CD24lo population, enhanced mammosphere formation, and upregulation of
ALDH expression and enzymatic activity. Furthermore, the CD44hi/CD24lo
population also shows positive correlation with LMW-E expression in both the tumor
cell line model and breast cancer patient samples (p<0.0001 & p=0.0435,
respectively). Combination treatment using doxorubicin and salinomycin
demonstrates synergistic cytotoxic effects in cells with LMW-E expression but not in
those with full-length cyclin E expression. Finally, ProtoArray microarray identifies
Hbo1 as a novel substrate of the cyclin E/CDK2 complex and its overexpression
results in enrichment for CSCs. Collectively, these data emphasize the strong
oncogenic potential of LMW-E in mammary tumorigenesis and suggest possible
therapeutic strategies to treat breast cancer patients with high LMW-E expression.
","abstract_html":"<p>Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that</p> <p>mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in</p> <p>breast cancer generates two low molecular weight (LMW) isoforms that exhibit both</p> <p>enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress</p> <p>LMW-E and associate with poor survival. Therefore, we <strong><em>hypothesize </em></strong>that <em>LMW-E</em></p> <p><em>disrupts normal mammary acinar morphogenesis and serves as the initial route into</em></p> <p><em>breast tumor development. </em>We first demonstrate that LMW-E overexpression in</p> <p>non-tumorigenic hMECs is sufficient to induce tumor formation in athymic mice</p> <p>significantly more than overexpression of full-length cyclin E and requires CDK2-</p> <p>associated kinase activity. Further <em>in vivo </em>passaging of these tumors augments</p> <p>LMW-E expression and tumorigenic potential. When subjected to acinar</p> <p>morphogenesis <em>in vitro</em>, LMW-E mediates significant morphological disruption by</p> <p>generating hyperproliferative and multi-acinar complexes. Proteomic analysis of</p> <p>patient tissues and tumor cells with high LMW-E expression reveals that the</p> <p>activation of the b-Raf-ERK1/2-mTOR pathway in concert with high LMW-E</p> <p>expression predicts poor patient survival. Combination treatment using roscovitine</p> <p>(CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (b-raf inhibitor)</p> <p>effectively prevented aberrant acinar formation in LMW-E-expressing cells by</p> <p>inducing the G1/S cell cycle arrest. In addition, the LMW-E-expressing tumor cells</p> <p>exhibit phenotypes characteristic of the EMT and enhanced cellular invasiveness.</p> <p>These tumor cells also enrich for cells with CSC phenotypes such as increased</p> <p>CD44hi/CD24lo population, enhanced mammosphere formation, and upregulation of</p> <p>ALDH expression and enzymatic activity. Furthermore, the CD44hi/CD24lo</p> <p>population also shows positive correlation with LMW-E expression in both the tumor</p> <p>cell line model and breast cancer patient samples (p<0.0001 & p=0.0435,</p> <p>respectively). Combination treatment using doxorubicin and salinomycin</p> <p>demonstrates synergistic cytotoxic effects in cells with LMW-E expression but not in</p> <p>those with full-length cyclin E expression. Finally, ProtoArray microarray identifies</p> <p>Hbo1 as a novel substrate of the cyclin E/CDK2 complex and its overexpression</p> <p>results in enrichment for CSCs. Collectively, these data emphasize the strong</p> <p>oncogenic potential of LMW-E in mammary tumorigenesis and suggest possible</p> <p>therapeutic strategies to treat breast cancer patients with high LMW-E expression.</p>","abstract_has_math":false,"creators":["Duong, MyLinh T"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Khandan Keyomarsi, Ph.D.","Michelle Barton, Ph.D.","Mong-Hong Lee, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-05-01T07:00:00Z","date_published":"2012-05-01T07:00:00Z","updated_at":"2026-07-24T05:48:59Z","subjects":["cyclin E","breast cancer","acinar morphogenesis","roscovitine","b-Raf-ERK1/2-mTOR pathway","cancer stem cells","epithelial-mesenchymal transition","salinomycin","Hbo1","Cancer Biology","Laboratory and Basic Science Research"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/221","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Khandan Keyomarsi, Ph.D.","Michelle Barton, Ph.D.","Mong-Hong Lee, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Duong, MyLinh T"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2012-02-13T08:00:00Z"]},{"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":["cyclin E","breast cancer","acinar morphogenesis","roscovitine","b-Raf-ERK1/2-mTOR pathway","cancer stem cells","epithelial-mesenchymal transition","salinomycin","Hbo1","Cancer Biology","Laboratory and Basic Science Research"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/221"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that
mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in
breast cancer generates two low molecular weight (LMW) isoforms that exhibit both
enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress
LMW-E and associate with poor survival. Therefore, we hypothesize that LMW-E
disrupts normal mammary acinar morphogenesis and serves as the initial route into
breast tumor development. We first demonstrate that LMW-E overexpression in
non-tumorigenic hMECs is sufficient to induce tumor formation in athymic mice
significantly more than overexpression of full-length cyclin E and requires CDK2-
associated kinase activity. Further in vivo passaging of these tumors augments
LMW-E expression and tumorigenic potential. When subjected to acinar
morphogenesis in vitro, LMW-E mediates significant morphological disruption by
generating hyperproliferative and multi-acinar complexes. Proteomic analysis of
patient tissues and tumor cells with high LMW-E expression reveals that the
activation of the b-Raf-ERK1/2-mTOR pathway in concert with high LMW-E
expression predicts poor patient survival. Combination treatment using roscovitine
(CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (b-raf inhibitor)
effectively prevented aberrant acinar formation in LMW-E-expressing cells by
inducing the G1/S cell cycle arrest. In addition, the LMW-E-expressing tumor cells
exhibit phenotypes characteristic of the EMT and enhanced cellular invasiveness.
These tumor cells also enrich for cells with CSC phenotypes such as increased
CD44hi/CD24lo population, enhanced mammosphere formation, and upregulation of
ALDH expression and enzymatic activity. Furthermore, the CD44hi/CD24lo
population also shows positive correlation with LMW-E expression in both the tumor
cell line model and breast cancer patient samples (p<0.0001 & p=0.0435,
respectively). Combination treatment using doxorubicin and salinomycin
demonstrates synergistic cytotoxic effects in cells with LMW-E expression but not in
those with full-length cyclin E expression. Finally, ProtoArray microarray identifies
Hbo1 as a novel substrate of the cyclin E/CDK2 complex and its overexpression
results in enrichment for CSCs. Collectively, these data emphasize the strong
oncogenic potential of LMW-E in mammary tumorigenesis and suggest possible
therapeutic strategies to treat breast cancer patients with high LMW-E expression.
"]},{"key":"dc:title","label":"Title","values":["Lmw-E Mediates Mammary Tumorigenesis By Deregulating Acinar Morphogenesis & Generating Cancer Stem Cells"]}]}],"canonical_facts":{"dc:contributor":["Khandan Keyomarsi, Ph.D.","Michelle Barton, Ph.D.","Mong-Hong Lee, Ph.D."],"dc:creator":["Duong, MyLinh T"],"dc:date.available":["2012-02-13T08:00:00Z"],"dc:description.abstract":["Cyclin E is the regulatory subunit of the cyclin E/CDK2 complex that
mediates the G1-S phase transition. N-terminal cleavage of cyclin E by elastase in
breast cancer generates two low molecular weight (LMW) isoforms that exhibit both
enhanced kinase activity and resistance to p21 and p27 inhibition compared to fulllength cyclin E. Clinically, approximately 27% of breast cancer patients overexpress
LMW-E and associate with poor survival. Therefore, we hypothesize that LMW-E
disrupts normal mammary acinar morphogenesis and serves as the initial route into
breast tumor development. We first demonstrate that LMW-E overexpression in
non-tumorigenic hMECs is sufficient to induce tumor formation in athymic mice
significantly more than overexpression of full-length cyclin E and requires CDK2-
associated kinase activity. Further in vivo passaging of these tumors augments
LMW-E expression and tumorigenic potential. When subjected to acinar
morphogenesis in vitro, LMW-E mediates significant morphological disruption by
generating hyperproliferative and multi-acinar complexes. Proteomic analysis of
patient tissues and tumor cells with high LMW-E expression reveals that the
activation of the b-Raf-ERK1/2-mTOR pathway in concert with high LMW-E
expression predicts poor patient survival. Combination treatment using roscovitine
(CDK inhibitor) plus either rapamycin (mTOR inhibitor) or sorafenib (b-raf inhibitor)
effectively prevented aberrant acinar formation in LMW-E-expressing cells by
inducing the G1/S cell cycle arrest. In addition, the LMW-E-expressing tumor cells
exhibit phenotypes characteristic of the EMT and enhanced cellular invasiveness.
These tumor cells also enrich for cells with CSC phenotypes such as increased
CD44hi/CD24lo population, enhanced mammosphere formation, and upregulation of
ALDH expression and enzymatic activity. Furthermore, the CD44hi/CD24lo
population also shows positive correlation with LMW-E expression in both the tumor
cell line model and breast cancer patient samples (p<0.0001 & p=0.0435,
respectively). Combination treatment using doxorubicin and salinomycin
demonstrates synergistic cytotoxic effects in cells with LMW-E expression but not in
those with full-length cyclin E expression. Finally, ProtoArray microarray identifies
Hbo1 as a novel substrate of the cyclin E/CDK2 complex and its overexpression
results in enrichment for CSCs. Collectively, these data emphasize the strong
oncogenic potential of LMW-E in mammary tumorigenesis and suggest possible
therapeutic strategies to treat breast cancer patients with high LMW-E expression.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/221"],"dc:subject":["cyclin E","breast cancer","acinar morphogenesis","roscovitine","b-Raf-ERK1/2-mTOR pathway","cancer stem cells","epithelial-mesenchymal transition","salinomycin","Hbo1","Cancer Biology","Laboratory and Basic Science Research"],"dc:title":["Lmw-E Mediates Mammary Tumorigenesis By Deregulating Acinar Morphogenesis & Generating Cancer Stem Cells"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:59Z"}