Because insulin regulates glucose homeostasis, there has been extensive study into the molecular mechanisms of action of the insulin signaling system. Besides insulin, additional ligands, insulin-like growth factor (IGF) – I and –II and specific receptors for these ligands regulate cellular biology. The receptors share a similar structure and function. Once ligand binds the extracellular domain, a conformational change occurs allowing autophosphorylation of the intracellular tyrosine kinase domains and subsequent activation of multiple signaling pathways that ultimately result in cellular glucose uptake. Type 2 diabetes mellitus (T2D) results from deficient insulin receptor (InsR) signaling and subsequent elevation of serum glucose with compensatory attempt at regulating this pathophysiology by increased insulin production by the pancreas. While the etiology of T2D is complex and multi-factorial, obesity and insulin resistance are epidemiologically and mechanistically linked. Insulin was one of the first peptide growth factors known to stimulate breast cancer proliferation. Epidemiological data link obesity, metabolic syndrome (hyperinsulinemia), and elevated levels of IGFs to breast cancer risk and poor outcome for women diagnosed with breast cancer. These data, in part, led to the development of multiple targeted therapies for breast cancer. Receptor targeting of IGF-receptor signaling was not successful in hormone receptor (HR) positive breast cancers possibly because drugs designed to target this receptor disrupted the negative feedback of this endocrine system and resulted in the elevation of serum insulin levels. Since InsR was not affected by anti-IGF receptor drugs, the potential that InsR was stimulated by these drug treatments could explain their failure. In contrast to receptor targeting strategies, the inhibition of downstream signaling pathways, such as mTORC1, have been successful in HR-positive breast cancer. Preclinical and clinical data have revealed complex intracellular and endocrine feedback pathways that affect the ability of any single targeted drug to effectively disrupt signals from this ligand-receptor family. This session will discuss combination strategies based on clinical and preclinical studies that could translate into effective drug therapies to disrupt this signaling system.

Citation Format: Yee D. Role for IGF/Insulin signaling in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr ES9-1.