title: Inhibition of p300 suppresses growth of breast cancer. Role of p300 subcellular localization.
abstract: There is evidence that p300, a transcriptional co-factor and a lysine acetyl-transferase, could play a role both as an oncoprotein and as a tumor suppressor, although little is known regarding its role in breast cancer (BC). First we investigated the role p300 has on BC by performing pharmacological inhibition of p300 acetyl-transferase function and analyzing the effects on cell count, migration and invasion in LM3 murine breast cancer cell line and on tumor progression in a syngeneic murine model. We subsequently studied p300 protein expression in human BC biopsies and evaluated its correlation with clinical and histopathological parameters of the patients. We observed that inhibition of p300 induced apoptosis and reduced migration and invasion in cultured LM3 cells. Furthermore, a significant reduction in tumor burden, number of lung metastases and number of tumors invading the abdominal cavity was observed in a syngeneic tumor model of LM3 following treatment with the p300 inhibitor. This reduction in tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. Moreover, the analysis of p300 expression in human BC samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and the rate of cytoplasmic p300 was higher in BC than in non-tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a longer overall survival time of the patients. In conclusion, we demonstrated that inhibition of the acetylase function of p300 reduces both cell count and invasion in LM3 cells, and decreases tumor progression in the animal model. In addition, we show that the presence of p300 in the cytoplasm correlates with increased survival of patients suggesting that its nuclear localization is necessary for the pro-tumoral effects.
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: efermento@criba.edu.ar.
authors.forename: María E
authors.initials: ME
authors.lastname: Fermento
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: ngandini@uns.edu.ar.
authors.forename: Norberto A
authors.initials: NA
authors.lastname: Gandini
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: dsalomon@criba.edu.ar.
authors.forename: Débora G
authors.initials: DG
authors.lastname: Salomón
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: jferronato@criba.edu.ar.
authors.forename: María J
authors.initials: MJ
authors.lastname: Ferronato
authors.affiliation: Departamento de Química, Instituto de Química del Sur (INQUISUR-CONICET), Universidad Nacional del Sur, Av. Alem 1253, 8000 Bahía Blanca, Argentina. Electronic address: cvitale@criba.edu.ar.
authors.forename: Cristian A
authors.initials: CA
authors.lastname: Vitale
authors.affiliation: Servicio de Patología del Hospital Interzonal General de Agudos Dr. José Penna, Av. Lainez 2401, 8000 Bahía Blanca, Argentina. Electronic address: arevalo_julian@hotmail.com.
authors.forename: Julián
authors.initials: J
authors.lastname: Arévalo
authors.affiliation: Departamento de Hematología, IACA, San Martín 68, 8000 Bahía Blanca, Argentina. Electronic address: hematologia@iaca.com.ar.
authors.forename: Alejandro
authors.initials: A
authors.lastname: López Romero
authors.affiliation: Cátedra de Matemática, Departamento de Físico-Matemática, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Viamonte 444, C1053ABJ Ciudad autónoma de Buenos Aires, Argentina. Electronic address: myr1710@yahoo.com.
authors.forename: Myriam
authors.initials: M
authors.lastname: Nuñez
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs University Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. Electronic address: manfred.jung@pharmazie.uni-freiburg.de.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: facchinm@criba.edu.ar.
authors.forename: María M
authors.initials: MM
authors.lastname: Facchinetti
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca, Centro Científico Tecnológico (INIBIBB-CCT-CONICET), Camino La Carrindanga Km. 7, 8000 Bahía Blanca, Argentina. Electronic address: acurino@criba.edu.ar.
authors.forename: Alejandro C
authors.initials: AC
authors.lastname: Curino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000502:physiology; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal
chemical_list: D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: Animal model; Breast cancer; Cell line; Human biopsies; p300