טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentRostoker Ran
SubjectThe Mechanisms Involved in the Enhanced Risk for Breast
Cancer Associated with Hyperinsulinemia
DepartmentDepartment of Medicine
Supervisors Professor Emeritus Derek Leroith
Dr. Maty Zukerman
Full Thesis textFull thesis text - English Version


Abstract

Epidemiological and experimental studies have identified hyperinsulinemia as an important risk factor for breast cancer induction and for the poor prognosis in breast cancer patients with obesity and Type 2 diabetes. Recently it was demonstrated that both the insulin receptor (IR) and the insulin-like growth factor-I receptor (IGF1R) mediate hyperinsulinemia’s mitogenic effect in several breast cancer models. Whereas IGF1R has been intensively investigated, IR role in mediating hyperinsulinemia’s mitogenic effect remains to be clarified. Here, we aimed to explore and isolate the therapeutic potential of targeting IR by two different approaches, systemic inhibition and tumor-specific down-regulation of IR. To initiate breast tumors, we have inoculated the mammary carcinoma Mvt-1 cell line into the inguinal mammary fat pad of the hyperinsulinemic MKR female mice, and to study the role of IR we first treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well documented IGF1R inhibitor picropodophyllin (PPP).  While systemically reducing IR activation, with resultant severe hyperglycemia and hyperinsulinemia, S961 treated mice had significantly larger tumors compared to the vehicle treated group. This effect maybe secondary to the severe hyperinsulinemia mediated via the IGF1 receptor.  In contrast, PPP by partially inhibiting both IR and IGF1R activity reduced tumor growth rate with only mild metabolic consequences.

Unlike targeting IR in a systemic fashion, we highlight the role of the IR in mediating breast tumor progression in both wild-type (WT) mice and in the hyperinsulinemic MKR mice model by induction of IR or IGF1R knock-down (KD) in a tumor-specific manner . By using S961, we demonstrated that IGF1R-KD induces elevated responses by the IR to IGF1.  The tumorigenic effects of insulin on the Mvt-1 cells was also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, cell cycle and apoptosis following insulin stimulation. In addition, we highlighte the importance of CD24 as a marker for isolating highly tumorigenic and metastatic breast cancer cells. Moreover, we demonstrate   positive correlation between IR and CD24 expression, and suggeste that CD24 expression may predict the cellular response to a variety of ligands. Taken together, our results highlight the role of IR in mammary tumor progression. We suggest that both IR and IGF1R should be targeted in order to accomplish a significant inhibitory effect on tumor growth, however such a strategy should be done in parallel with constant monitoring of blood glucose level.