Inhibiting breast cancer by targeting the thromboxane A₂ pathway

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.