Misregulation of lymphatic valve development by impaired BMP signalling as potential risk factor for development of breast-cancer related lymphedema

The growing population of breast cancer survivors has resulted in an increased focus on management and early prevention of acute and chronic side-effects of cancer treatment like breast cancer related lymphedema (BCRL). BCRL is a progressive condition that can result in chronic swelling of the arm with irreversible changes. BCRL can have a detrimental impact on the quality of life of breast cancer survivors, and often requires life-long palliative care. Risk factors for BCRL include increased BMI, type of surgery and radiotherapy, and genetic predisposition factors are also at play. We postulate impaired BMP signaling as new predisposition factor of BCRL. Indeed, the BMP signaling pathway has recently been shown to regulate development of the lymphatic system, and impaired BMP signalling results in lymphedema in animal models. Yet, the precise function of BMP signalling in human lymphatic vessels remains unclear. Our present data in mice indicate a
functional role for the intracellular BMP effectors, SMAD1/5, in lymphatic valves development and regulation of flow. We will further investigate how SMAD1/5 proteins molecularly regulate
lymphatic valve maturation. Furthermore, we will test our central hypothesis in tissue samples of cancer patients collected during surgery and correlate results with BCRL development/progression.
This work can result in better diagnosis and earlier treatment of of subclinical lymphedema with consequently less disturbing therapy and improved outcome.