Abstract
Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically.
Highlights
Breast cancer is the most commonly diagnosed cancer in women [1] and the majority of breast tumors are hormone-responsive [2]
A second OVX and letrozole (OVX-Let)-treated group was treated with the bisphosphonate zoledronic acid (Zol, 5μ/kg 3x/ week) in order to determine the relative importance of bone loss on tumor growth and muscle function in the setting of Aromatase inhibitors (AIs) therapy (Figure 1)
Increased bone resorption has been demonstrated in preclinical models, including OVX, to accelerate cancer progression in bone [30,31,32] presumably via release of matrix-derived growth factors, (e.g., TGFβ, IGF, FGF, PDGF), which stimulate tumor growth and expression of osteolytic factors that perpetuate a feed-forward cycle of bone destruction [20]
Summary
Breast cancer is the most commonly diagnosed cancer in women [1] and the majority of breast tumors are hormone-responsive [2]. Adjuvant endocrine therapies that impair the action of estrogen on breast tissue have become an important treatment strategy, reducing the risk of recurrence and death in women with estrogen receptor (ER)-positive disease [3,4,5]. Aromatase inhibitors, which block the rate-limiting step of estrogen biosynthesis [6], have replaced selective estrogen receptor modulators (SERMs; e.g., tamoxifen) as the standard of care in postmenopausal breast cancer patients due to improved disease-free survival [7, 8]. Our laboratory has had a longstanding interest in investigating how bone loss can impact tumor behavior in the bone microenvironment, a question that is of relevance to breast cancer patients undergoing prolonged AI therapy in the absence of a bone-protective intervention
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