Inhibiting breast cancer by targeting the thromboxane A(2) 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 A(2) synthase 1 or the thromboxane A(2) receptor is highly expressed in human breast tumors as well as premalignant lesions, but not in normal mammary tissues. Clinically, the thromboxane A(2) pathway might be associated with HER2-positive and axillary lymph node metastasis in human breast cancer. We found that the thromboxane A(2) pathway was required for breast cancer cell growth, anchorage-independent growth and invasion capabilities. Importantly, we discovered that switching off thromboxane A(2) 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 A(2) pathway in breast cancer, and provided a rationale for introducing a strategy targeting thromboxane A(2) for breast cancer chemoprevention and therapy.