title: PACE4 is an important driver of ZR-75-1 estrogen receptor-positive breast cancer proliferation and tumor progression.
abstract: Breast cancer is the most frequent and deadly malignancy in women worldwide. Despite national screening programs combined with new treatments relapse rate remain high and new therapies are needed. From previous work, we identified PACE4, a member of the proprotein convertase (PCs) family of endoproteases, as a novel therapeutic target in prostate cancer. In the present study we asked the question if PACE4 could also be a potential target in breast cancer. In clinical samples of breast adenocarcinoma, we observed a specific overexpression of PACE4 in the estrogen-receptor (ER) positive subtype. We therefore looked for a breast cancer cell line model which would be representative and thus focused on the ZR-75-1 since it both expresses PACE4 and is estrogen-receptor positive. We compared stable knockdowns of furin, PACE4 and PC7 in the estrogen-receptor-positive cell line ZR-75-1 to evaluate their respective contribution to cell growth and tumor progression. PACE4 was the only PC displaying an impact on cell growth. A PACE4 peptide-based inhibitor (C23) was tested and shown to decrease proliferation of ZR-75-1 cells in cell based assays. C23 also had potent effects of tumor progression in vivo on xenografts of the ZR-75-1 cell line in athymic nude mice. Thus, PACE4-silencing and systemic administration of a PACE4 inhibitor resulted in hindered tumor progression with reduction in proliferative indices and increased cell quiescence assessed with biomarkers. Our results suggest that PACE4 is a promising target for estrogen-receptor-positive breast cancer.
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Department of Surgery, Division of Urology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Panet
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Department of Surgery, Division of Urology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Couture
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Department of Surgery, Division of Urology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Department of Surgery, Division of Urology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada.
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Centre de recherche clinique Étienne-Le Bel, Department of Nuclear Medicine and Radiobiology, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Guérin
authors.affiliation: Institut de pharmacologie de Sherbrooke, Canada; Department of Surgery, Division of Urology, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, Quebec, Canada. Electronic address: robert.day@usherbrooke.ca.
authors.forename: Robert
authors.initials: R
authors.lastname: Day
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D043484:Proprotein Convertases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: Breast cancer; PACE4; Proprotein convertase; ZR-75-1