Role of Bone-Derived TGF-beta in Glucose Metabolism in the Setting of Breast Cancer Bone Metastases
Abstract
Rationale: Bone metastasis is one of the most severe consequences of breast cancer: it causes pain, pathological fracture, spinal cord compression, and muscle weakness. But the most devastating complication is that once the tumor spreads to bone, it is incurable. Patients with diabetes have increased risk of developing cancer, and cancer patients with diabetes and obesity have poor outcomes and reduced survival. Recent studies show that bone is an endocrine organ, which regulates whole body glucose homeostasis. However, the influence of diabetes and obesity, which often occur together, on tumor growth of breast cancer bone metastases is unknown. Moreover, factors released from bone, particularly TGF-beta during states of bone loss, are known to stimulate breast cancer growth in bone (metastases), and our data demonstrate that TGF-beta released from the bone can impair glucose metabolism in mice and cause muscle weakness. The proposed studies will test the hypothesis that bone destruction releases a growth factor, TGF-beta, to produce oxidative stress in beta-cells in pancreas that abnormally opens calcium (Ca2+) release channels, called RyR2 (Ryanodine Receptor), and result in impaired insulin release from beta-cells to cause high blood glucose and potentially diabetes. Overarching Challenges: (1) Eliminate mortality associated with breast cancer: Defective glucose metabolism, bone loss, and muscle weakness as a result of excess TGF-beta released from bone can cause devastating complications of cancer to reduce quality of life and survival of breast cancer patients. We propose to test novel pancreatic-beta cell specific drugs that could improve glucose metabolism in breast cancer patients with bone metastases. We also propose to test drugs that block TGF-beta release/activity, stabilize calcium leak together with low-intensity vibration (LIV) therapy on preservation of bone health, muscle strength, and normal blood glucose. (2) Identify what drives breast cancer growth; determine how to stop it. Our proposed studies aim to evaluate how bone-derived TGF-beta, by mediating defective insulin release and glucose metabolism, prime the bone microenvironment in a way that can accelerate deadly breast cancer bone metastases. Novel therapeutics, as proposed, can reduce tumor growth and improve bone loss and glucose metabolism to improve survival of the patients with breast cancer. Scientific Objectives: We propose that bone-derived TGF-beta causes diabetes by reducing insulin release from pancreatic beta-cells to promote breast cancer growth in bone in conditions of obesity and aging. Aim 1: Using a mouse model of breast cancer bone metastases, obesity, and aging, we will demonstrate that bone-derived TGF-beta impairs glucose metabolism and exacerbates bone metastases. Inhibition of TGF-beta release and signaling in combination with LIV will be tested for improvement in glucose metabolism, bone loss, muscle strength, and tumor growth. Aim 2: Using the similar bone metastases model as in Aim 1, changes in bone and beta-cell insulin release particularly, destabilization of RyR2, will be evaluated as well as tumor progression. Rycal drugs (S107; a molecule that stabilizes RyR2 to prevent calcium leak) will be tested with LIV on insulin release from pancreatic beta-cells, bone metabolism and tumor growth in bone. Aim 3 will assess blood, bone, muscle, and tumor from breast cancer patients with bone metastases to validate findings on glucose metabolism, muscle function, and tumor growth in bone from the mouse models. Applicability: These studies can quickly be applied to breast cancer patients. Next to nothing is known about the impact of bone-derived factors on glucose metabolism in patients with breast cancer bone metastases. The proposed research will investigate, whether bone-derived TGF-beta acts on pancreatic-beta cells to impair insulin secretion and glucose metabolism through a specific molecular mech
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810678
Entities
People
- Theresa Guise
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army