ABSTRACT
Inheritance of a BRCA2 pathogenic variant conveys a substantial life-time risk of breast cancer. Identification of the cell(s)-of-origin of BRCA2-mutant breast cancer and targetable perturbations that contribute to transformation remains an unmet need for these individuals who frequently undergo prophylactic mastectomy. Using preneoplastic specimens from age-matched, premenopausal females, here we show broad dysregulation across the luminal compartment in BRCA2mut/+ tissue, including expansion of aberrant ERBB3lo luminal progenitor and mature cells, and the presence of atypical oestrogen receptor (ER)-positive lesions. Transcriptional profiling and functional assays revealed perturbed proteostasis and translation in ERBB3lo progenitors in BRCA2mut/+ breast tissue, independent of ageing. Similar molecular perturbations marked tumours bearing BRCA2-truncating mutations. ERBB3lo progenitors could generate both ER+ and ER- cells, potentially serving as cells-of-origin for ER-positive or triple-negative cancers. Short-term treatment with an mTORC1 inhibitor substantially curtailed tumorigenesis in a preclinical model of BRCA2-deficient breast cancer, thus uncovering a potential prevention strategy for BRCA2 mutation carriers.
Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/genetics , Breast Neoplasms/prevention & control , Mastectomy , Mutation , BRCA2 Protein/genetics , Carcinogenesis , Cell Transformation, Neoplastic , BRCA1 Protein/geneticsABSTRACT
Se procura establecer la incidencia de hongos anemófilos en la ciudad de Córdoba durante un año; se evalúa la influencia de los factores climáticos (temperatura, viento, humedad y presión atmosférica), los cambios atribuibles a la naturaleza del suelo, la vegetación y al progreso edilicio de la ciudad. Verano: presentan su pico de mayor frecuencia dentro de los Deuteromycotina: Fusarium, Oospora, Micelia Sterilia y Gliocladium; en Zygomicotina: Rhizopus y en Ascomycotina las Levaduras. Otoño: se aislan con mayor frecuencia los géneros Helminthosporium, Pullularia, Monotospora, Monilia y Trichoderma. Invierno: los géneros predominantes son Penicillium, Hormodendrum y Cephalosporium. Primavera: presentan su pico de mayor frecuencia Alternaria, Cladosporium, Nigrospora, Aspergillus y Acremonium. Estos registros fueron comparados mediante tablas estadísticas con un trabajo similar efectuado hace dos décadas y se obtuvieron diferencias ampliamente significativas atribuibles al aumento en las clases Zygomicotina y Deuteromycotina, no ocurrió lo mismo para la clase de los Ascomycotina