Abstract
Breast cancer patients, who are already at increased risk of developing bone metastases and osteolytic bone damage, are often treated with doxorubicin. Unfortunately, doxorubicin has been reported to induce damage to bone. Moreover, we have previously reported that doxorubicin treatment increases circulating levels of TGFβ in murine pre-clinical models. TGFβ has been implicated in promoting osteolytic bone damage, a consequence of increased osteoclast-mediated resorption and suppression of osteoblast differentiation. Therefore, we hypothesized that in a preclinical breast cancer bone metastasis model, administration of doxorubicin would accelerate bone loss in a TGFβ-mediated manner. Administration of doxorubicin to 4T1 tumor-bearing mice produced an eightfold increase in osteolytic lesion areas compared untreated tumor-bearing mice (P = 0.002) and an almost 50% decrease in trabecular bone volume expressed in BV/TV (P = 0.0005), both of which were rescued by anti-TGFβ antibody (1D11). Doxorubicin, which is a known inducer of oxidative stress, decreased osteoblast survival and differentiation, which was rescued by N-acetyl cysteine (NAC). Furthermore, doxorubicin treatment decreased Cu-ZnSOD (SOD1) expression and enzyme activity in vitro, and treatment with anti-TGFβ antibody was able to rescue both. In conclusion, a combination therapy using doxorubicin and anti-TGFβ antibody might be beneficial for preventing therapy-related bone loss in cancer patients.
Highlights
More than one million new cases of breast cancer are diagnosed worldwide annually
Our data indicate that doxorubicin treatment significantly (P,0.001) increased osteolytic lesion area and lesion numbers compared to the control group (Figure 1G, H), suggesting that treatment with doxorubicin further increases bone destruction in tumor-bearing mice
Despite several reports of the damaging effect of doxorubicin on bone cells, not much was known about whether treatment with this agent may accelerate bone loss in breast cancer patients, who are already suffering from osteolytic disease
Summary
More than one million new cases of breast cancer are diagnosed worldwide annually. A major clinical complication of metastatic breast cancer is osteolytic bone destruction, and more than 75% of patients suffer from osteolysis, leading to increased fracture risk and poor quality of life. While local bone resorption can be induced by the cancer cells at the metastatic site, commonly used cancer therapies often cause additional rapid and systemic bone loss, posing a major challenge in the long term management of patients with breast cancer. Buttiglieri et al have recently reported that doxorubicin treatment in cultured human mesenchymal stem cells reduced clonogenic ability and decreased osteoblast differentiation, accompanied by increased adipogenic potential [10]. These adverse effects heighten the concern for breast cancer patients who have received doxorubicin as a part of their treatment regimen, because these patients are already at high risk for bone loss and pathological fracture
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