RESUMEN
Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
Asunto(s)
Apoptosis , Benzamidas/farmacología , Proteínas Ricas en Prolina del Estrato Córneo/fisiología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Neoplasias Endometriales/tratamiento farmacológico , Nitrilos/farmacología , Fosfohidrolasa PTEN/fisiología , Feniltiohidantoína/farmacología , Animales , Proliferación Celular , Neoplasias Endometriales/genética , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Masculino , Ratones , Ratones Noqueados , Transducción de Señal , Carga TumoralRESUMEN
We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of TP53 and that R72 increases the risk for angiomyolipoma. R72 transactivates NOTCH1 and NODAL better than the proline variant of codon 72 (P72); therefore, the expression of NOTCH1 and NODAL is increased in angiomyolipoma cells that carry R72. The loss of Tp53 and Tsc1 within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high Notch1 and Nodal expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine Tp53 or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways. IMPLICATIONS: This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling.
Asunto(s)
Carcinogénesis/patología , Proteína Nodal/metabolismo , Polimorfismo de Nucleótido Simple , Receptor Notch1/metabolismo , Esclerosis Tuberosa/patología , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/fisiología , Angiomiolipoma/genética , Angiomiolipoma/metabolismo , Angiomiolipoma/patología , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Movimiento Celular , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Ratones , Mutación , Proteína Nodal/genética , Receptor Notch1/genética , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Proteína 1 del Complejo de la Esclerosis Tuberosa/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Differentiation abnormalities are a hallmark of tuberous sclerosis complex (TSC) manifestations; however, the genesis of these abnormalities remains unclear. Here we report on mechanisms controlling the multi-lineage, early neuronal progenitor and neural stem-like cell characteristics of lymphangioleiomyomatosis (LAM) and angiomyolipoma cells. These mechanisms include the activation of a previously unreported Rheb-Notch-Rheb regulatory loop, in which the cyclic binding of Notch1 to the Notch-responsive elements (NREs) on the Rheb promoter is a key event. This binding induces the transactivation of Rheb. The identified NRE2 and NRE3 on the Rheb promoter are important to Notch-dependent promoter activity. Notch cooperates with Rheb to block cell differentiation via similar mechanisms in mouse models of TSC. Cell-specific loss of Tsc1 within nestin-expressing cells in adult mice leads to the formation of kidney cysts, renal intraepithelial neoplasia, and invasive papillary renal carcinoma.
