Intracellular aggregated TRPV1 is associated with lower survival in breast cancer patients

Carlo Lozano,1–3 Claudio Córdova,1 Ivanny Marchant,1,2 Rodrigo Zúñiga,3 Paola Ochova,3 Ricardo Ramírez-Barrantes,4 Wilfredo Alejandro González-Arriagada,2,5 Belén Rodriguez,1 Pablo Olivero1,2 1Laboratorio de Estructura y Función Celular, Escuela de Medicina, Facultad de Medicina, Universidad de Valparaíso, Hontaneda, Valparaíso, Chile; 2Centro Interoperativo en Ciencias Odontológicas y Médicas, Universidad de Valparaíso, Valparaíso, Chile; 3Servicio de Anatomía Patológica, Hospital Carlos van Buren, San Ignacio, Valparaíso, Chile; 4Escuela de Tecnologia Medica, Universidad Andres Bello, Quillota, Viña del Mar, Chile; 5Patología y Diagnóstico Oral, Facultad de Odontología, Universidad de Valparaíso, Valparaíso, Chile Background: Breast cancer is a malignant disease that represents an important public health burden. The description of new molecular markers can be important to diagnosis, classification, and treatment. Transient receptor potential vanilloid 1 (TRPV1) polymodal channel is expressed in different neoplastic tissues and cell lines of breast cancer and associated with the regulation of tumor growth, tumor neurogenesis, cancer pain, and malignant progression of cancer. In primary and metastatic breast cancer tumors, TRPV1 is expressed during neoplastic transformation, invasive behavior, and resistance to cytotoxic therapy.Objective: The objective of this study was to describe the subcellular distribution of TRPV1 in invasive breast carcinomas and its association with survival.Methods: In 33 cases of invasive breast carcinomas, we identified immunohistochemical and immunofluorescent expression patterns of TRPV1 compared to healthy breast tissue. We characterized the expression of TRPV1 induced by estrogens in breast cancer cell lines MCF-7 and MDA to establish a model of the TRPV1–estrogen relationship regarding the malignant potential. We examined the association of TRPV1 patterns with patients’ survival with the Kaplan–Meyer model, using the log-rank test at 5 years of follow-up. The relation of TRPV1 expression patterns to the St. Gallen breast cancer subtypes was also tested.Results: Based on immunohistochemical expression pattern of TRPV1, we distinguished two main categories of breast cancer tissue, a “classical category” that exhibited diffuse expression of the channel and a “non-classical category” that expressed the channel in aggregates at the ER/Golgi and/or surrounding these structures. The classical pattern of TRPV1 was associated with a higher survival rate. In breast cancer cell lines, increasing doses of estrogens induced increased TRPV1 expression with nonclassical patterns at higher doses via a mechanism dependent on ER α.Conclusion: The expression and distribution of TRPV1 in invasive breast carcinomas may be considered as a biomarker for prognosis of the disease and a probable therapeutic target. Keywords: immunohistochemistry, breast cancer, capsaicin receptors, vanilloid receptors, breast cancer prognosi