Abstract
Targeting the estrogen receptor as a strategy has been the gold standard for breast cancer chemoprevention or breast cancer recurrence, but its benefit is limited to estrogen receptor-positive tumors. Cyclooxygenases have been implicated in mammary tumorigenesis. We sought to identify the key prostaglandin responsible for the pro-neoplastic effect of cyclooxygenases and develop prostaglandin-targeted strategies for breast cancer chemoprevention or therapy. Immunohistochemical analysis revealed that either thromboxane A2 synthase 1 or the thromboxane A2 receptor is highly expressed in human breast tumors as well as premalignant lesions, but not in normal mammary tissues. Clinically, the thromboxane A2 pathway might be associated with HER2-positive and axillary lymph node metastasis in human breast cancer. We found that the thromboxane A2 pathway was required for breast cancer cell growth, anchorage-independent growth and invasion capabilities. Importantly, we discovered that switching off thromboxane A2 biosynthesis effectively suppressed either MMTV-HER2-driven mammary tumorigenesis or breast cancer metastasis in preclinical animal models. Taken together, this study established a critical pathophysiological role of the thromboxane A2 pathway in breast cancer, and provided a rationale for introducing a strategy targeting thromboxane A2 for breast cancer chemoprevention and therapy.