Anti-Insulin Resistance Treatments Suppress Her2+ Breast Cancer Growth Via Altering Metabolism

<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⁺ 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 (<em>Lepr </em>^db/+) and MMTV-ErbB2 (<em>neu</em>) mice. The MMTV-ErbB2/<em>Lepr </em>^db/db mice had a poor survival rate compared with MMTV-ErbB2/<em>Lepr </em>^+/+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>^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/<em>Lepr </em>^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 <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>^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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• CHOU, PING-CHIEH

Contributors dc:contributor

• Mong-Hong Lee
• Min Gyu Lee
• Hui-Kuan Lin

• HER2
• breast cancer
• DM2
• diabetes treatment
• metformin
• rosiglitazone
• metabolism
• insulin resistant
• Cancer Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/450

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1489