RESUMEN
Receptor Activator of NF-kappa B (RANK) pathway controls mammary gland development in mice but its role in mammary stem cell fate remains undefined. We show that constitutive RANK signaling expands luminal and basal mammary compartments including mammary stem and luminal progenitor cell pools and interferes with the generation of CD61+ and Sca1+ luminal cells and Elf5 expression. Impaired mammary cell commitment upon RANK overexpression leads to the accumulation of progenitors including K14+K8+ bipotent cells and the formation of heterogeneous tumors containing hyperplastic basal, luminal, and progenitor cells. RANK expression increases in wild-type mammary epithelia with age and parity, and spontaneous preneoplastic lesions express RANK and accumulate K14+K8+ cells. In human breast tumors, high RANK expression levels are also associated with altered mammary differentiation. These results suggest that increased RANK signaling interferes with mammary cell commitment, contributing to breast carcinogenesis.
Asunto(s)
Carcinogénesis/patología , Linaje de la Célula , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Envejecimiento/patología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Compartimento Celular , Diferenciación Celular , Forma de la Célula , Epitelio/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Queratinas/metabolismo , Glándulas Mamarias Animales/metabolismo , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Virus del Tumor Mamario del Ratón/fisiología , Ratones , Modelos Biológicos , Paridad , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Embarazo , Receptor Activador del Factor Nuclear kappa-B/genética , Células Madre/metabolismoRESUMEN
CONTEXT: The sodium iodide symporter (NIS) mediates active transport of iodide into the thyroid and the lactating mammary glands and is highly expressed in thyroid and breast carcinomas. NIS is clinically very relevant because it allows the treatment with radioiodine of thyroid cancer patients. OBJECTIVE: In this study we wanted to explore whether NIS is expressed in the ovary and in ovarian cancer. METHODS/PATIENTS: Methods included NIS and paired box 8 expression and function in ovarian cancer patients and rats by immunochemistry, immunoblot, RT-PCR, and iodide uptake. RESULTS: Here we demonstrate for the first time that NIS is expressed in the ovary and fallopian tube and actively accumulates significant levels of radioiodide in vivo. In a large survey of menstruating women receiving radioiodide for medical purposes, 15% showed significant uptake in the normal reproductive tract. Ovarian NIS activity is influenced by the estrous cycle stage in rats, being up-regulated during peak levels of estrogens occurring immediately before the ovulation. We unveil that the regulatory mechanism underlying this phenomenon is based on the functional cooperation of estrogen receptor-α and paired box 8. We also show that NIS is highly expressed in ovarian cancer, predicting a poor prognosis in these patients. CONCLUSIONS: These results provide the basis that will help minimize the impact of therapeutic doses of radioiodide on gonadal function. We also suggest that NIS is a new ovarian cancer marker, opening a door for the use of radioiodide in the diagnosis and treatment of ovarian cancer patients.