The Role of PAQR8 in Breast Cancer Recurrence and Therapy Resistance
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Translational Research
Treatment Resistance
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Abstract
Breast cancer is the most common cancer and leading cause of cancer-related deaths among women worldwide. Despite recent advances in therapies that significantly improve survival rates, recurrent disease due to therapy resistance continues to account for breast cancer mortality. Here, we explore a novel mechanism of therapy resistance that frequently occurs across all subtypes of breast cancer. Copy number (CN) gain of the putative membrane progesterone receptor PAQR8 was one of four focal CN alterations that preferentially occurred in recurrent metastatic tumors compared to primary tumors in breast cancer patients enrolled in the METAMORPH study. Whether PAQR8 plays a functional role in cancer is unknown. Notably, PAQR8 CN gain in recurrent tumors was mutually exclusive with activating ESR1 mutations in patients treated with anti-estrogen therapies, and occurred in >50% of both patients treated with anti-estrogen therapies and those treated with chemotherapy or anti-Her2 agents. Experimentally, we show that PAQR8 is necessary and sufficient for mammary tumor recurrence in mice, spontaneously upregulated and CN gained in post-therapy recurrent tumors from multiple mouse models, and associated with breast cancer progression and poor survival in patients. PAQR8 promoted therapy resistance by enhancing tumor cell survival following estrogen receptor pathway inhibition by fulvestrant or estrogen deprivation, Her2 pathway blockade by lapatinib or Her2 downregulation, or treatment with chemotherapeutic agents. Pro-survival effects of PAQR8 were mediated by a Gi protein-dependent reduction in cAMP levels, did not require progesterone, and involved a PAQR8-dependent decrease in ceramide levels and increase in sphingosine-1-phosphate levels, suggesting that PAQR8 may possess ceramidase activity. Together, our data provide in vivo evidence that PAQR8 plays a functional role in cancer, implicate PAQR8, cAMP, and ceramide metabolism in breast cancer recurrence, and identify a novel mechanism that could contribute to >50% of treatment resistance in breast cancer patients.
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Murphy, Maureen, E