Reduced DPP9 levels sensitize experimental breast tumors to combinatory treatment with irradiation and Olaparib

Breast cancer is a heterogenous disease with various molecular subtypes. Among these, triple-negative breast cancer has the worst prognosis due to its high aggressiveness and limited availability of targeted therapies. In breast cancers, reduced expression of dipeptidyl peptidase 9 (DPP9) is associated with a poor patient prognosis. To model reduced DPP9 expression, we transplanted the human triple-negative breast cancer cell line MDA.MB.231 with an inducible genetic DPP9 deficiency in the mammary fat pad of immunocompromised mice. As expected, tumors with DPP9 deficiency showed an increased weight as well as more lung metastasis compared to controls. This phenotype seems to be promoted by increased vessel formation in the tumor due to DPP9 deficiency. Upon irradiation (2 × 9 Gy), tumor growth was initially reduced independent of DPP9 expression, although DPP9-deficient tumors grew out faster after irradiation compared to controls. Additionally, more metastases were formed in mice with DPP9-deficient tumors compared to controls as well as untreated mice with tumors of both genotypes. As proteolytic cleavage of BRCA2 by DPP9 was previously shown to promote repair of DNA double-strand breaks by homologous recombination, the poly-ADP-ribose-polymerase (PARP) inhibitor Olaparib (25 mg/kg) was applied to mice in combination with local irradiation in order to test for synthetic lethality effects. The results revealed further reduction in tumor growth compared to untreated and irradiated mice. Furthermore, DPP9 deficiency together with combined irradiation/PARP inhibition further reduced tumor growth compared to control tumors. Yet, metastasis formation presented with a mixed outcome in mice with DPP9-deficient tumors. In summary, reduced DPP9 levels enhanced primary tumor growth but sensitized triple-negative breast tumors to a combination of irradiation and Olaparib.