| Breast cancer (BCa) is the most frequently diagnosed non-cutaneous cancer in the United States and the second leading cause of cancer death of American women. Over the last several decades, enhancement of BCa screening and early detection improved patients survival rate and patients' well-being. However, some aggressive types of BCa still threaten BCa patients' well- being. Triple negative breast cancer (TNBC) is one of the most aggressive types of breast cancer and needs new promising therapeutic agents due to its lack in responsiveness to hormonal therapies or HER2 targeting drugs due to the absence of progesterone receptor, estrogen receptor, and HER2 receptor. Therefore, developing novel therapeutic agents and/or strategies aimed to prevent TNBC growth and to attenuate its behavior associated with metastasis will at improve patients' well-being ultimately cure the disease. ATP was considered originally as only an intracellular energy source. The concept that ATP is an extracellular messenger was not widely accepted until its receptors was cloned in early 1990s. Subsequently, purinergic signaling was investigated and its association with cell growth and proliferation was discovered. One of ATP analogs, 2&feet;, 3&feet;-O-(4-benzoylbenzoyl)-ATP (BzATP) showed wide range of both in vitro and in vivo tumor suppression such as cell proliferation inhibition and apoptosis induction.;The inhibitory effects on cell proliferation, cell migration, and cell invasion of adenine nucleotides and other adenine agents on BCa were observed in vitro. Colony formation assay revealed a suppression of adenine nucleotides especially BzATP on ability of TNBC cells to form colonies. The pilot in vivo experiment demonstrated tumor growth inhibition effect of BzATP in vivo. These in vivo data confirmed an inhibitory effect of BzATP on TNBC tumor growth in vitro. P2Y11 was identified as a receptor mediating inhibitory effect of BzATP. Further analysis on cell death mechanism revealed that BzATP induced ER stress, autophagy and apoptosis, but not necrosis, through P2Y11 receptor. Unlike autophagy reported in many literatures that it is survival pathway cancer cells exploited to avoid apoptosis, BzATP-induced autophagy may not be a survival mechanism. Remarkably, BzATP did not induce apoptosis in non-cancerous mammary epithelial cells, MCF10A. |
