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Research

Insulin/IGF1 signaling in cancer progression

Obesity, a growing health epidemic, is associated with increased risk of both developing and dying from breast cancer.  A major consequence of obesity is insulin resistance, leading to hyperinsulinemia.  Although several factors have been implicated in contributing to the increased cancer risk due to obesity, imagenmz8m.pnghyperinsulinemia is an independent risk factor for breast cancer initiation and recurrence.   Elevated insulin levels have also been implicated in tumor drug resistance, including resistance to PI3K targeted inhibitors and hormonal therapy.   High insulin levels can stimulate both the insulin receptor (IR) and the closely related insulin-like growth factor-1 receptor (IGF-1R), both of which have been implicated in breast cancer initiation and progression.  Unfortunately, adverse metabolic side-affects limit the ability to aggressively co-target the IR and IGF-1R.  We aim to develop a greater understanding of downstream signaling through the IR/IGF-1R to determine how to target these essential signaling pathways in cancer without interfering with their roles in normal metabolic homeostasis.

Insulin Receptor Substrate (IRS) protein function

The IRS imagekvfcu.pngproteins are cytoplasmic adaptor proteins that mediate signals from the IR and IGF-1R to regulate organismal growth and metabolic homeostasis.  Our in vivo studies to investigate the function of IRS-1 and IRS-2 in mammary tumor development and progression to metastasis revealed that IRS-1 and IRS-2 play divergent roles in mammary tumor metastasis. Mammary tumors that lack IRS-2 are significantly diminished in their ability to metastasize and tumors lacking IRS-1, and expressing only IRS-2, have enhanced metastatic potential.  Our research has been directed toward understanding the molecular mechanisms by which these homologous proteins differentially impact breast cancer progression. Our studies have revealed that IRS-2 plays a dominant role in tumor progression through its involvement in regulating tumor cell invasion and metabolism.  The ability of IRS2 to promote invasion is dependent upon upstream IGF-1R/IR activation and the recruitment and activation of PI3K.  In addition, we identified a region within the IRS2 C-terminal tail that is both necessary and sufficient for promoting tumor cell invasion. Importantly, this “INV region” is not required for the IRS2-dependent regulation of glucose uptake, providing evidence that IRS functions important for cancer progression can be disrupted while preserving the normal metabolic functions of these adaptor proteins.  Ongoing research in the lab focuses on investigating the mechanistic basis for differential IRS contributions to IR/IGF-1R signaling and tumor progression using cellular, biochemical, structural and molecular approaches.

Beclin 1 regulation of receptor trafficking

Beclin 1 is a haploinsufficient tumor suppressor that has
been implicated in breast cancer development and progression.  The function of Beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy.  We identified an alternative mechanism of action for Beclin 1 in breast cancer involving its control of growth factor receptor trafficking and signaling.  We discovered that Beclin 1 promotes endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which is necessary for sorting surface receptors to intraluminal vesicles for signal silencing and lysosomal degradation.  In tumors with low Beclin 1 expression, endosomal HRS recruitment is diminished and the extended residency time of growth factor receptors in the early endosome compartment sustains the longevity of downstream signals.  A consequence of this prolonged expression and function is increased tumor proliferation.  We are interested in exploring further how this mechanism of Beclin 1 action can provide insight into the clinical management of tumors with low Beclin 1 expression.