Role of ACER2 in cancer chemoresistance and metastasis

Neoadjuvant chemotherapy (NAC) has become an increasingly popular treatment approach for breast cancer (BC) patients. It enables locally advanced and inflammatory BC patients to be eligible for breast conservative surgery. However, emerging evidence suggests that preoperative NAC may paradoxically increase the risk of BC cancer chemoresistance and progression, thus limiting its therapeutic efficacy. The specific goals of this application are to define a novel role for alkaline ceramidase 2 (ACER2) in mediating NAC-induced chemoresistance and metastasis of BC and to develop this concept into novel therapeutic approaches to improving BC therapy. ACER2 is a member in the alkaline ceramidase family that we identified initially from the yeast Saccharomyces cerevisiae and then from mammals. ACER2 catalyzes the hydrolysis of ceramide to generate sphingosine (SPH), which is immediately converted to sphingosine-1-phosphate (S1P), a bioactive lipid that has been implicated in tumor angiogenesis and lymphangiogenesis, protumoral immune responses, and cancer stem cell survival. Our preliminary studies demonstrate that doxorubicin (DOX), a chemotherapeutic agent commonly used in BC patients, induces a marked increase in the levels of S1P in in the tumor, primary site of the tumor (mammary fat pads), and major metastatic tissues of BC (brain, bone marrow, liver, and lungs) in a syngeneic mouse model of BC. We further show that knocking out the mouse alkaline ceramidase 2 gene (Acer2) from host cells markedly inhibits DOX-induced increase in the levels of S1P in the tumor and the aforementioned tissues, robustly augments DOX-induced tumor growth inhibition, and inhibits DOX-induced pulmonary metastasis of BC. These compelling results support our hypothesis that NAC-induced upregulation of the ACER2/S1P pathway mediates BC chemoresistance and metastasis. As a further corollary, we hypothesize that blocking the ACER2/S1P pathway with an ACER2 inhibitor (ACER2i) will improve the therapeutic efficacy of chemotherapeutic agents against BC by mitigating chemotherapy-induced chemoresistance and metastasis of BC. To test these hypotheses, we will 1) establish that ACER2 mediates NAC-induced chemoresistance and metastasis of BC (Aim 1); 2) Define the molecular and cellular mechanisms by ACER2 mediates NAC-induced chemoresistance and metastasis (Aim 2); and 3) Establish that targeting ACER2 with its small molecule inhibitor (ACER2i) would mitigate NAC-induced chemoresistance and metastasis of BC and thereby improves NAC of BC (Aim 3). Successful completion of these aims will 1) validate the pathological role of the ACER2/S1P pathway in cancer chemoresistance, metastasis, and recurrence; and 2) provide a proof of concept that targeting the ACER2 pathway would improve BC chemotherapy. Given the poor clinical outcome of patients with most cancers, these studies may have widespread impact on the clinical management of these patients.