RESUMEN
ATM kinase is a gatekeeper of genome stability. However, its role in several other signaling pathways suggests that it might not always act as a tumor suppressor. Here, we discuss recent data that unveil a function of ATM as a tumor promoter in HER2-positive breast cancer.
RESUMEN
ATM kinase preserves genomic stability by acting as a tumour suppressor. However, its identification as a component of several signalling networks suggests a dualism for ATM in cancer. Here we report that ATM expression and activity promotes HER2-dependent tumorigenicity in vitro and in vivo. We reveal a correlation between ATM activation and the reduced time to recurrence in patients diagnosed with invasive HER2-positive breast cancer. Furthermore, we identify ATM as a novel modulator of HER2 protein stability that acts by promoting a complex of HER2 with the chaperone HSP90, therefore preventing HER2 ubiquitination and degradation. As a consequence, ATM sustains AKT activation downstream of HER2 and may modulate the response to therapeutic approaches, suggesting that the status of ATM activity may be informative for the treatment and prognosis of HER2-positive tumours. Our findings provide evidence for ATM's tumorigenic potential revising the canonical role of ATM as a pure tumour suppressor.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias de la Mama/genética , Carcinogénesis/genética , Carcinoma/genética , Receptor ErbB-2/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma/metabolismo , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Células HEK293 , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Inmunohistoquímica , Técnicas In Vitro , Células MCF-7 , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Trasplante de Neoplasias , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Adulto JovenRESUMEN
Ataxia-telangiectasia mutated (ATM) kinase is a one of the main guardian of genome stability and plays a central role in the DNA damage response (DDR). The deregulation of these pathways is strongly linked to cancer initiation and progression as well as to the development of therapeutic approaches. These observations, along with reports that identify ATM loss of function as an event that may promote tumor initiation and progression, point to ATM as a bona fide tumor suppressor. The identification of ATM as a positive modulator of several signalling networks that sustain tumorigenesis, including oxidative stress, hypoxia, receptor tyrosine kinase and AKT serine-threonine kinase activation, raise the question of whether ATM function in cancer may be more complex. This review aims to give a complete overview on the work of several labs that links ATM to the control of the balance between cell survival, proliferation and death in cancer.
