Date of Graduation
5-2014
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Mong-Hong Lee
Committee Member
Min Gyu Lee
Committee Member
Hui-Kuan Lin
Committee Member
Dos Sarbassov
Committee Member
Sai-Ching Jim Yeung
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.
Keywords
HER2, breast cancer, DM2, diabetes treatment, metformin, rosiglitazone, metabolism, insulin resistant