Effect of Low-Magnitude Mechanical Signals on Breast Cancer Bone Metastases
Abstract
Rationale: The musculoskeletal system (muscle and bone) is particularly sensitive to endocrine or hormone therapy, which is a standard of care for breast cancer patients with estrogen-sensitive tumors. Aromatase inhibitors (AIs) reduce the circulating levels of estrogen (E2) in the body and thus prevent E2-dependent growth of breast cancer. Unfortunately, up to half of women treated with AIs experience severe musculoskeletal complications, including muscle weakness and bone loss, that result in treatment discontinuation. Our preliminary data indicate that E2 deficiency and bone loss are associated with impaired muscle contraction and alterations to the ryanodine receptor (RyR1), a calcium (Ca2+) channel in skeletal muscle, which regulates Ca2+ necessary for muscle contraction. Moreover, in mice, AI-treatment causes bone loss and increases ER-negative breast cancer bone metastases due to factors released from bone. Exercise effectively prevents muscle and bone loss, resulting from cancer and its associated therapies; however, even minimally strenuous activities can induce severe fatigue or increase fracture risk, thereby exacerbating the very condition its intended to curtail. Low intensity vibration (LIV) delivers very small magnitude forces that increase skeletal formation and muscle strength. Such mechanical signals restrict the bone loss associated with ovarian cancer and multiple myeloma in mice, and even reduce cancer progression; however, the effects of LIV on breast cancer and AI-induced musculoskeletal deterioration are unknown. Our proposed studies will evaluate LIV as a surrogate exercise treatment to ameliorate muscle weakness, bone loss, and prevent breast cancer bone metastases. Additionally, the mechanism enabling force transmission to musculoskeletal and breast cancer cells will be determined. Overarching Challenges: (1) Eliminate mortality associated with metastatic breast cancer. Our proposed translational studies aim to evaluate how LIV treatment can suppress breast cancer metastasis and the negative musculoskeletal effects of AI-induced E2 deprivation. (2) Identify what drives breast cancer growth and determine how to stop it. Factors released during a state of E2 deprivation-induced bone resorption can reverse disseminated cancer cell dormancy and cause recurrence. We will test whether LIV alone or in combination with an anti-resorptive drug can prevent disseminated cancer cells from developing into overt tumors in bone. (3) Revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective. Discontinuation of anti-E2 therapy due to musculoskeletal toxicities increases the risk of cancer mortality. We propose to evaluate a safe and effective musculoskeletal-specific treatment that could improve muscular strength and bone density in cancer patients and improve compliance with life-prolonging adjuvant anti-estrogen therapy. Scientific Objectives: We hypothesize that low intensity vibration, alone or in combination with an anti-resorptive bone agent, can prevent bone and muscle loss resulting from breast cancer or E2 depletion therapy. Aim 1: We will determine if LIV and/or an anti-resorptive bone agent prevents deterioration of bone and muscle weakness in AI-treated mice inoculated with human breast cancer cells. We will also examine the effectiveness of LIV to reduce breast cancer progression. Aim 2: We will demonstrate that LIV alone or in combination with an antiresorptive bone drug restricts the bone loss and muscle weakness associated with estrogen deprivation therapy and determine if LIV mechanical signals influence structural features of the musculoskeletal cells that enhance transmission of force. Aim 3: To examine how LIV signals mediate their anabolic and anti-cancer effects, E2-deprived mice with breast cancer and lacking a gene that enables LIV force transmission will be vibrated. Research Impa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610040
Entities
People
- Theresa Guise
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army