Breast Cancer Lymphedema: Role of Insulin Resistance/FOXC2

Lymphedema of the arm is an important, under-recognized, and under-treated complication of
successful surgical and radiotherapeutic treatment of breast cancer. As a result of advances
in early detection and effective adjuvant therapies, many women diagnosed with breast cancer
today can expect survival that is similar to age-matched women without breast cancer.
Nevertheless, this source of substantial physical and psychological morbidity has not
attracted sufficient attention from industry or the scientific research community to result
in either effective risk stratification or the availability highly effective therapeutic
interventions.

While the presence and degree of arm edema can, in part, correlated with the extent of
axillary surgery, we still comprehend only poorly the factors that predispose to overt
lymphatic insufficiency in the patients at risk for lymphedema by virtue of prior breast
cancer treatment. It is likely that this anatomic and regenerative variability relies, at
least in part, upon an as yet undefined genetic substrate. A growing body of evidence
suggests that mutations in the nuclear transcription gene FOXC2 are responsible for a broad
clinical array of primary lymphedema syndromes. The biology of breast cancer-associated
lymphedema, including its characteristic latency phase, suggests that similar mechanisms may
operate in the predisposition to this and other forms of secondary lymphedema.

In parallel, breast cancer-associated lymphedema has several clinical attributes that
suggest a relationship to, and a role for, insulin resistance. In this regard, it is
interesting to contemplate the recent, multiple lines of evidence that suggest that the gene
FOXC2 regulates, directly or indirectly, several aspects of adipocyte metabolism and that
genetic variability in the gene may influence features associated with the insulin
resistance and the metabolic syndrome. These observations are of particular interest because
of the recognized relationship of FOXC2 haploinsufficiency to a variety of identified
lymphedema syndromes. It is therefore attractive to conjecture that insulin resistance,
perhaps mediated through polymorphisms of FOXC2,.confers secondary lymphedema risk and
predisposes to the as yet poorly understood tendency for breast cancer survivors to acquire
substantial, pathological deposits of adipose tissue in the affected extremities with
chronicity of the lymphedema.

The specific aims of this proposal are as follows: (1) to quantitatively assess insulin
sensitivity in late breast cancer survivors, equally divided among subjects who display
clinical evidence of ipsilateral arm edema and those that do not; (2) to correlate the
presence of relative insulin resistance to the expression of breast cancer-associated
lymphedema. It is hypothesized that such an approach has the capability to lead to future
elaboration of appropriate risk stratification and targeted therapeutic interventions; (3)
as a pilot investigation, to sequence the FOXC2 gene, including the untranslated 5' region,
in each these patients, to identify potential polymorphisms that might correlate both to the
presence of insulin resistance and lymphedema risk.