Low molecular weight cyclin E (LMW-E) are oncogenic forms of cyclin E that are post translationally generated by neutrophil elastase (NE) mediated cleavage of the 50 KDa full-length cyclin E1 (FL-cycE, encoded by CCNE1gene). The resultant N-terminus deleted (40 amino acids) form of LMW-E is detected in breast cancer cells and tumor tissues, but not in normal mammary epithelial cells or adjacent normal tissues. Unlike FL-cycE, LMW-E drives mammary epithelial cell transformation in human cells and spontaneous mammary tumor formation in transgenic mouse models, but the oncogenic mechanisms of LMW-E and its unique function(s) independent of FL-cycE are not fully understood. It is currently assumed that LMW-E drives the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Biochemical features such as longer protein half-life, higher affinity to its kinase partner CDK2, and resistance to endogenous CDK inhibitors such as p21 and p27 all promote the tumorigenic ability of LMW-E. Clinical studies in breast cancer reveal that overexpression of LMW-E predicts recurrence and poor survival in breast cancer patients independent of molecular subtype, Ki67 status, nodal status, or tumor grade, suggesting LMW-E may be driving breast cancer development independent of its role in cell proliferation.
In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) engineered to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background. We found that, unlike LMW-E, FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E but not FL-cycE strongly interacted with CDC6, bound to chromatin, and facilitated replication stress tolerance by upregulating pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating the levels of RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development.
Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers.
","abstract_html":"<p>Low molecular weight cyclin E (LMW-E) are oncogenic forms of cyclin E that are post translationally generated by neutrophil elastase (NE) mediated cleavage of the 50 KDa full-length cyclin E1 (FL-cycE, encoded by <em>CCNE1</em>gene). The resultant N-terminus deleted (40 amino acids) form of LMW-E is detected in breast cancer cells and tumor tissues, but not in normal mammary epithelial cells or adjacent normal tissues. Unlike FL-cycE, LMW-E drives mammary epithelial cell transformation in human cells and spontaneous mammary tumor formation in transgenic mouse models, but the oncogenic mechanisms of LMW-E and its unique function(s) independent of FL-cycE are not fully understood. It is currently assumed that LMW-E drives the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Biochemical features such as longer protein half-life, higher affinity to its kinase partner CDK2, and resistance to endogenous CDK inhibitors such as p21 and p27 all promote the tumorigenic ability of LMW-E. Clinical studies in breast cancer reveal that overexpression of LMW-E predicts recurrence and poor survival in breast cancer patients independent of molecular subtype, Ki67 status, nodal status, or tumor grade, suggesting LMW-E may be driving breast cancer development independent of its role in cell proliferation.</p> <p>In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) engineered to express doxycycline inducible LMW-E or FL-cycE in <em>CCNE1</em> knock-out background. We found that, unlike LMW-E, FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E but not FL-cycE strongly interacted with CDC6, bound to chromatin, and facilitated replication stress tolerance by upregulating pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating the levels of RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development.</p> <p>Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers.</p>","abstract_has_math":false,"creators":["Li, Mi","https://orcid.org/0000-0002-6038-4144
"],"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.","Junjie Chen, Ph.D.","Sendurai Mani, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2023,"date_issued":"2023-02-01T08:00:00Z","date_published":"2023-02-01T08:00:00Z","updated_at":"2026-07-24T05:50:16Z","subjects":["Low molecular weight cyclin E","cell cycle","DNA replication","DNA damage repair","genomic instability","copy number variation","CCNE1","CDC6","ATR-CHK1-RAD51","breast cancer","Cancer Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1237","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.","Junjie Chen, Ph.D.","Sendurai Mani, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Li, Mi","https://orcid.org/0000-0002-6038-4144
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In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) engineered to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background. We found that, unlike LMW-E, FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E but not FL-cycE strongly interacted with CDC6, bound to chromatin, and facilitated replication stress tolerance by upregulating pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating the levels of RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development.
Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers.
"]},{"key":"dc:title","label":"Title","values":["Low Molecular Weight Cyclin E Deregulates Dna Replication and Damage Repair to Promote Genomic Instability In Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Khandan Keyomarsi, Ph.D.","Junjie Chen, Ph.D.","Sendurai Mani, Ph.D."],"dc:creator":["Li, Mi","https://orcid.org/0000-0002-6038-4144
"],"dc:date.available":["2023-01-11T08:00:00Z"],"dc:description.abstract":["Low molecular weight cyclin E (LMW-E) are oncogenic forms of cyclin E that are post translationally generated by neutrophil elastase (NE) mediated cleavage of the 50 KDa full-length cyclin E1 (FL-cycE, encoded by CCNE1gene). The resultant N-terminus deleted (40 amino acids) form of LMW-E is detected in breast cancer cells and tumor tissues, but not in normal mammary epithelial cells or adjacent normal tissues. Unlike FL-cycE, LMW-E drives mammary epithelial cell transformation in human cells and spontaneous mammary tumor formation in transgenic mouse models, but the oncogenic mechanisms of LMW-E and its unique function(s) independent of FL-cycE are not fully understood. It is currently assumed that LMW-E drives the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Biochemical features such as longer protein half-life, higher affinity to its kinase partner CDK2, and resistance to endogenous CDK inhibitors such as p21 and p27 all promote the tumorigenic ability of LMW-E. Clinical studies in breast cancer reveal that overexpression of LMW-E predicts recurrence and poor survival in breast cancer patients independent of molecular subtype, Ki67 status, nodal status, or tumor grade, suggesting LMW-E may be driving breast cancer development independent of its role in cell proliferation.
In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) engineered to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background. We found that, unlike LMW-E, FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E but not FL-cycE strongly interacted with CDC6, bound to chromatin, and facilitated replication stress tolerance by upregulating pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating the levels of RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development.
Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1237"],"dc:subject":["Low molecular weight cyclin E","cell cycle","DNA replication","DNA damage repair","genomic instability","copy number variation","CCNE1","CDC6","ATR-CHK1-RAD51","breast cancer","Cancer Biology"],"dc:title":["Low Molecular Weight Cyclin E Deregulates Dna Replication and Damage Repair to Promote Genomic Instability In Breast Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:16Z"}