BREAST CANCER LYMPHEDEMA: ROLE OF INSULIN RESISTANCE/FOXC2

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: It is hypothesized that: 1) a quantitative assessment of insulin sensitivity in late breast cancer survivors, equally divided among subjects who display clinical evidence of ipsilateral arm edema and those that do not, and 2) correlation of the presence of relative insulin resistance (IR) to the expression of breast cancer-associated lymphedema, will lead to future elaboration of appropriate risk stratification and targeted therapeutic interventions. Additionally, we will sequence the FOXC2 gene, including the untranslated 5' region, in each patient to identify potential polymorphisms that might correlate both to the presence of IR and lymphedema risk. Experimental Design: In the initial visit, each study subject will undergo clinical assessment of general health, including a physical examination, and evaluation of upper extremity volume, estimated from tape measurements of limb circumference. A peripheral blood sample will be obtained for analysis of the FOXC2 gene. In the second visit, assessment of insulin sensitivity will be performed. The ability of insulin to promote glucose uptake will be estimated by a modification of the insulin suppression test (IST) as originally described. After an overnight fast, octreotide in a solution containing 2.5% (w/v) human serum albumin will be administered at a rate of 25 ¿g/hr by a Harvard infusion pump, to suppress endogenous insulin secretion. Simultaneously, insulin and glucose will be infused at 25 mU/m2/min and 240 mg/m2/min, respectively. Blood will be sampled every half hour until 150 min into the test, and then every ten min in the last 30 min of the test. In the third (last) visit, each subject will undergo a standard oral glucose tolerance test. After an overnight fast, a 75 g oral glucose load will be administered, with subsequent venous blood collection at times 0, 30, 60, 120, and 180 min.