Human Tamm-Horsfall protein as a novel antitumor therapy for triple negative breast cancer and other solid tumors

Renal Tamm-Horsfall protein (THP) -the most abundant protein excreted in urine- can modulate urinary tract innate and adaptive immune responses. Despite the lack of prior research into THP's antitumor effects, here we examined the impact of urinary THP (urTHP) on proliferation, survival and migration of 4T1 murine triple-negative breast cancer (TNBC), MDA-MB-231 human TNBC, and CT-26 murine colon cancer cell lines. We also assessed urTHP's antitumor properties by using the 4T1 and CT-26 tumor models in BALB/c mice, urTHP's potential to limit metastasis and its effects on survival rates when combined with docetaxel. We found that urTHP significantly impaired 4T1, CT-26 and MDA-MB-231 in vitro cell proliferation, migration and survival. However, urTHP did not restrict the proliferation of MCF-10A -a non-tumorigenic human breast cell line- but it induced tumor cell necrosis. urTHP (3 mg/kg) administration to mice reduced 4T1 tumor growth in a T-cell-dependent manner. Administration of urTHP combined with 15 mg/kg docetaxel enhanced urTHP's antimetastatic effect against 4T1 or CT-26 tumors and improved mice survival rates compared with chemotherapy alone. Our results uncover urTHP's antitumor and antimetastatic effects in preclinical models, and provide a proof-of-concept for its administration as an adjuvant for chemotherapy to improve outcomes in the metastatic setting.