Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2+ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2+ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr db/db mice had a poor survival rate compared with MMTV-ErbB2/Lepr +/+ mice, and the log rank test of the Kaplan-Meier analysis showed that they were significantly different (P = 0.0004). In addition, we evaluated the impact of different anti-diabetic medications on cancer-specific survival. MMTV-ErbB2/Lepr db/db mice administrated with metformin or rosiglitazone showed improved overall survival, cumulative tumor incidence, and reduced tumor progression. Anti-insulin resistance treatments can also reverse the Warburg effect by reducing lactate/pyruvate ratio through 13C-pyruvate imaging. Cell lines isolated from MMTV-ErbB2/Lepr db/db mice also showed reduced levels of both oxygen consumption and lactate production upon metformin treatment. Metformin treatment not only inhibited proliferation and induced apoptosis in Human HER2+ breast cancer cell lines, but also repressed c-MYC mRNA expression, increased proteasome-dependent degradation, and reduced the downstream key glycolysis enzyme PKM2. Moreover, anti-insulin resistance treatments dramatically change the microenvironment by reducing serum insulin levels and this systematic effect attenuated the mTOR/AKT signaling pathway in tumor samples from MMTV-ErbB2/Lepr db/db mice. Anti-insulin resistance treatments also affected adipokine expression profiles and may reveal potential targets for further research. In conclusion, our results indicate the therapeutic effect of anti-insulin resistance treatments on breast cancer metabolism and this animal model also shed the light on the clinical implications of anti-insulin resistance treatments on HER2+ breast cancer patients accompanied with the DM2 condition.
","abstract_html":"<p>Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2<sup>+</sup> breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2<sup>+</sup> breast cancer with DM2 by crossing leptin receptor point mutation (<em>Lepr </em><sup>db/+</sup>) and MMTV-ErbB2 (<em>neu</em>) mice. The MMTV-ErbB2/<em>Lepr </em><sup>db/db</sup> mice had a poor survival rate compared with MMTV-ErbB2/<em>Lepr </em><sup>+/+ </sup>mice, and the log rank test of the Kaplan-Meier analysis showed that they were significantly different (<em>P </em>= 0.0004). In addition, we evaluated the impact of different anti-diabetic medications on cancer-specific survival. MMTV-ErbB2/<em>Lepr </em><sup>db/db</sup> mice administrated with metformin or rosiglitazone showed improved overall survival, cumulative tumor incidence, and reduced tumor progression. Anti-insulin resistance treatments can also reverse the Warburg effect by reducing lactate/pyruvate ratio through <sup>13</sup>C-pyruvate imaging. Cell lines isolated from MMTV-ErbB2/<em>Lepr </em><sup>db/db</sup> mice also showed reduced levels of both oxygen consumption and lactate production upon metformin treatment. Metformin treatment not only inhibited proliferation and induced apoptosis in Human HER2<sup>+</sup> breast cancer cell lines, but also repressed <em>c-MYC</em> mRNA expression, increased proteasome-dependent degradation, and reduced the downstream key glycolysis enzyme PKM2. Moreover, anti-insulin resistance treatments dramatically change the microenvironment by reducing serum insulin levels and this systematic effect attenuated the mTOR/AKT signaling pathway in tumor samples from MMTV-ErbB2/<em>Lepr </em><sup>db/db</sup> mice. Anti-insulin resistance treatments also affected adipokine expression profiles and may reveal potential targets for further research. In conclusion, our results indicate the therapeutic effect of anti-insulin resistance treatments on breast cancer metabolism and this animal model also shed the light on the clinical implications of anti-insulin resistance treatments on HER2<sup>+</sup> breast cancer patients accompanied with the DM2 condition.</p>","abstract_has_math":false,"creators":["CHOU, PING-CHIEH"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Mong-Hong Lee","Min Gyu Lee","Hui-Kuan Lin"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-05-01T07:00:00Z","date_published":"2014-05-01T07:00:00Z","updated_at":"2026-07-24T05:48:47Z","subjects":["HER2","breast cancer","DM2","diabetes treatment","metformin","rosiglitazone","metabolism","insulin resistant","Cancer Biology","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/450","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Mong-Hong Lee","Min Gyu Lee","Hui-Kuan Lin"]},{"key":"dc:creator","label":"Author","values":["CHOU, PING-CHIEH"]}]},{"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":["HER2","breast cancer","DM2","diabetes treatment","metformin","rosiglitazone","metabolism","insulin resistant","Cancer Biology","Medicine and Health Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/450"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2+ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2+ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr db/db mice had a poor survival rate compared with MMTV-ErbB2/Lepr +/+ mice, and the log rank test of the Kaplan-Meier analysis showed that they were significantly different (P = 0.0004). In addition, we evaluated the impact of different anti-diabetic medications on cancer-specific survival. MMTV-ErbB2/Lepr db/db mice administrated with metformin or rosiglitazone showed improved overall survival, cumulative tumor incidence, and reduced tumor progression. Anti-insulin resistance treatments can also reverse the Warburg effect by reducing lactate/pyruvate ratio through 13C-pyruvate imaging. Cell lines isolated from MMTV-ErbB2/Lepr db/db mice also showed reduced levels of both oxygen consumption and lactate production upon metformin treatment. Metformin treatment not only inhibited proliferation and induced apoptosis in Human HER2+ breast cancer cell lines, but also repressed c-MYC mRNA expression, increased proteasome-dependent degradation, and reduced the downstream key glycolysis enzyme PKM2. Moreover, anti-insulin resistance treatments dramatically change the microenvironment by reducing serum insulin levels and this systematic effect attenuated the mTOR/AKT signaling pathway in tumor samples from MMTV-ErbB2/Lepr db/db mice. Anti-insulin resistance treatments also affected adipokine expression profiles and may reveal potential targets for further research. In conclusion, our results indicate the therapeutic effect of anti-insulin resistance treatments on breast cancer metabolism and this animal model also shed the light on the clinical implications of anti-insulin resistance treatments on HER2+ breast cancer patients accompanied with the DM2 condition.
"]},{"key":"dc:title","label":"Title","values":["Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism"]}]}],"canonical_facts":{"dc:contributor":["Mong-Hong Lee","Min Gyu Lee","Hui-Kuan Lin"],"dc:creator":["CHOU, PING-CHIEH"],"dc:date.available":["2015-05-02T07:00:00Z"],"dc:description.abstract":["Epidemiological studies have identified that type 2 diabetes mellitus (DM2) is a significant risk factor for carcinogenesis and cancer death, including breast cancer. Our previous finding in patients showed that anti-insulin resistance treatments are associated with improved HER2+ breast cancer survival of diabetic women. However, there were no transgenic mouse models to study the correlation and explain the detailed mechanism. We generated a mouse model of HER2+ breast cancer with DM2 by crossing leptin receptor point mutation (Lepr db/+) and MMTV-ErbB2 (neu) mice. The MMTV-ErbB2/Lepr db/db mice had a poor survival rate compared with MMTV-ErbB2/Lepr +/+ mice, and the log rank test of the Kaplan-Meier analysis showed that they were significantly different (P = 0.0004). In addition, we evaluated the impact of different anti-diabetic medications on cancer-specific survival. MMTV-ErbB2/Lepr db/db mice administrated with metformin or rosiglitazone showed improved overall survival, cumulative tumor incidence, and reduced tumor progression. Anti-insulin resistance treatments can also reverse the Warburg effect by reducing lactate/pyruvate ratio through 13C-pyruvate imaging. Cell lines isolated from MMTV-ErbB2/Lepr db/db mice also showed reduced levels of both oxygen consumption and lactate production upon metformin treatment. Metformin treatment not only inhibited proliferation and induced apoptosis in Human HER2+ breast cancer cell lines, but also repressed c-MYC mRNA expression, increased proteasome-dependent degradation, and reduced the downstream key glycolysis enzyme PKM2. Moreover, anti-insulin resistance treatments dramatically change the microenvironment by reducing serum insulin levels and this systematic effect attenuated the mTOR/AKT signaling pathway in tumor samples from MMTV-ErbB2/Lepr db/db mice. Anti-insulin resistance treatments also affected adipokine expression profiles and may reveal potential targets for further research. In conclusion, our results indicate the therapeutic effect of anti-insulin resistance treatments on breast cancer metabolism and this animal model also shed the light on the clinical implications of anti-insulin resistance treatments on HER2+ breast cancer patients accompanied with the DM2 condition.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/450"],"dc:subject":["HER2","breast cancer","DM2","diabetes treatment","metformin","rosiglitazone","metabolism","insulin resistant","Cancer Biology","Medicine and Health Sciences"],"dc:title":["Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:48:47Z"}