Investigating new therapeutic strategies targeting hyperinsulinemia's mitogenic effects in a female mouse breast cancer model.

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 IGF-IR mediate hyperinsulinemia's mitogenic effect in several breast cancer models. Although IGF-IR has been intensively investigated, and anti-IGF-IR therapies are now in advanced clinical trials, the role of the IR in mediating hyperinsulinemia's mitogenic effect remains to be clarified. Here we aimed to explore the potential of IR inhibition compared to dual IR/IGF-IR blockade on breast tumor growth. To initiate breast tumors, we 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 treated the mice bearing tumors with the recently reported high-affinity IR antagonist-S961, in addition to the well-documented IGF-IR inhibitor picropodophyllin (PPP). Although 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 IGF-1 receptor. In contrast, PPP by partially inhibiting both IR and IGF-IR activity reduced tumor growth rate with only mild metabolic consequences. We conclude that targeting (even partially) both IR and IGF-IRs impairs hyperinsulinemia's effects in breast tumor development while simultaneously sparing the metabolic abnormalities observed when targeting IR alone with virtual complete inhibition.

• Authors: Ran Rostoker, Keren Bitton-Worms, Avishay Caspi, Zila Shen-Orr, Derek LeRoith
• Journal: Endocrinology (Endocrinology) Vol. 154 Issue 5 Pg. 1701-10 (May 2013) ISSN: 1945-7170 [Electronic] United States
• PMID: 23515289 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Growth Substances
• Insulin
• Peptides
• S961 peptide
• picropodophyllin
• Receptor, IGF Type 1
• Podophyllotoxin

Topics

• Animals
• Breast Neoplasms (complications, genetics, pathology, therapy)
• Carcinoma (complications, genetics, pathology, therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Female
• Growth Substances (adverse effects)
• Hyperinsulinism (complications, drug therapy, genetics, pathology)
• Insulin (adverse effects)
• Mammary Neoplasms, Experimental (complications, genetics, pathology, therapy)
• Mice
• Mice, Transgenic
• Molecular Targeted Therapy (methods)
• Peptides (therapeutic use)
• Podophyllotoxin (analogs & derivatives, therapeutic use)
• Receptor, IGF Type 1 (antagonists & inhibitors, genetics)
• Therapies, Investigational (methods)