CPSF6 is a Clinically Relevant Breast Cancer Vulnerability Target : Role of CPSF6 in Breast Cancer

Abstract

Breast cancer represents a major health challenge. The majority of breast cancer deaths are due to cancer progression/recurrence for which no efficient therapies exist. Aggressive breast cancers are characterized by loss of cellular differentiation. Defining molecular mechanisms/targets contributing to cancer aggressiveness is needed to guide the design of new screening and targeted treatments. Here, we describe a novel tumor promoting function for the Cleavage and Polyadenylation Factor-6 (CPSF6). Importantly, aggressive breast cancer cells of luminal B, HER2-overexpressing and triple negative subtypes show dependency on CPSF6 for viability and tumorigenic capacity. Mechanistically, we found CPSF6 to interact with components of the A-to-I RNA editing machinery, paraspeckles and ADAR1 enzyme, and to be required for their physical integrity. Clinically, we found CPSF6 and all core paraspeckles proteins to be overexpressed in human breast cancer cases and their expression to correlate with poor patient outcomes. Finally, we found prolactin, a key mammary differentiation factor, to suppress CPSF6/RNA editing activity. Together, this study revealed CPSF6 as a molecular target with clinical relevance for prognosis and therapy in breast cancer.

Highlights

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  Aggressive breast cancer cells require CPSF6 for viability and tumorigenesis.

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  CPSF6 and paraspeckles core proteins are associated with poor outcome in breast cancer.

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  Prolactin hormone reprograms cells to suppress CPSF6 interaction with paraspeckles and ADAR1, A-I RNA editing machinery.

Breast tumors of luminal B, HER2-enriched, and basal (triple negative) subtypes are associated with poor differentiation and aggressive behavior. Defining targets contributing to cancer aggressiveness may offer new modalities for prognosis and therapy. This study demonstrated the critical role of CPSF6 for survival and tumorigenic capacity of aggressive breast cancer cells. CPSF6 is required for the physical integrity of the A-to-I RNA editing complex, paraspeckles and ADAR1 enzyme. CPSF6 and core paraspeckles proteins are biomarkers of poor patient outcome. In addition, prolactin hormone was found to suppress CPSF6 function. This study highlights CPSF6 as a therapeutic target in breast cancer.