Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy

// Elenae Vazquez-Ulloa 1 , Ana Clara Ramos-Cruz 2 , Diddier Prada 2, 3 , Alejandro Aviles-Salas 4 , Alma Delia Chavez-Blanco 2 , Luis A. Herrera 2, 5 , Marcela Lizano 2, 5 and Adriana Contreras-Paredes 2 1 Programa de Maestria y Doctorado en Ciencias Bioquimicas, Universidad Nacional Autonoma de Mexico, Ciudad Universitaria, Mexico City, Mexico 2 Unidad de Investigacion Biomedica en Cancer, Instituto Nacional de Cancerologia-Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico 3 Departamento de Informatica Biomedica, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico 4 Departamento de Patologia Quirurgica, Instituto Nacional de Cancerologia, Mexico City, Mexico 5 Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico City, Mexico Correspondence to: Adriana Contreras-Paredes, email: adrycont@yahoo.com.mx Marcela Lizano, email: lizano@unam.mx Keywords: cervical cancer; cervical intraepithelial neoplasia; NOTCH1; NUMB; immunostaining Received: June 20, 2017      Accepted: February 24, 2018      Published: April 10, 2018 ABSTRACT The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerologia, Mexico from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (β = –3.428, 95% confidence interval [95% CI] = –5.127, –1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (β = 2.074, 95% [CI] = –0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression ( P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer.