Prognostic Implications of Numb Immunoreactivity in Salivary Gland Carcinomas

Abstract

The gene numb encodes for a protein (Numb) involved in cell fate decisions in Drosophila, with proposed endocytic and developmental functions in mammalians. The distribution pattern of Numb in human tissues however, has not been fully characterized. We set out to explore the immunohistochemical expression of Numb in normal and neoplastic (28 adenoid cystic and 34 mucoepidermoid carcinomas) salivary glands, and correlated the results with the clinico-pathologic features of the neoplasms. Intense Numb immunoreactivity was detected in normal ductal cells and in a subset of acinar cells. In salivary carcinomas, we detected diffuse and intense Numb immunostaining in 5 adenoid cystic and 8 mucoepidermoid carcinomas. By contrast, the majority of adenoid cystic and mucoepidermoid cancers showed only moderate (14 and 5 cases) or focal staining (9 and 21 cases), respectively. The corresponding expression of Numb mRNA was documented in normal parotid gland and adenoid cystic carcinoma. Numb immunoreactivity was inversely correlated with the histological grade and Ki-67 immunoreactivity of both adenoid cystic and mucoepidermoid carcinomas. In addition, while tumor grade, stage, Ki-67 and Numb immunoreactivity were associated with disease-free survival in univariate analysis, only Numb and Ki-67 immunoreactivities retained independent prognostic significance in multivariate analysis. These data suggest that loss of Numb is implicated in aberrant differentiation programs of salivary gland carcinomas and may serve as a prognostic indicator in patients treated for these neoplasms.

Overexpression of Numb suppresses tumor cell growth and enhances sensitivity to cisplatin in epithelioid malignant pleural mesothelioma

“…This suggests that loss of Numb expression is involved in the formation and development of epithelioid MPM. Negative Numb immunohistochemistry with poor prognosis was previously reported in human salivary gland carcinomas and breast tumors (12,24). Our data also showed that the reduction in Numb expression was associated with poor long term outcome in epithelioid MPM patients.…”

“…In addition, in vivo RNA interference of Numb in a model of mouse lymphomagenesis was found to accelerate the onset of lymphomas (23). Loss of Numb expression has also been reported in some types of human cancers, such as breast cancers, non-small cell lung carcinomas, salivary gland carcinomas and medulloblastomas (20,21,24,25). In human astrocytomas, there is a trend of higher Numb expression in more malignant tumors (26).…”

The tumor suppressive role of NUMB isoform 1 in esophageal squamous cell carcinoma

“…The relationship between NUMB and tumorigenesis was discovered in recent studies [12, 13] and accumulating evidence suggests a potential tumor suppressor role for NUMB, including stabilization of p53 [14, 15] and inhibition of Notch signaling [16, 17]. Indeed, these proposed tumor suppressive functions of NUMB are consistent with previous studies conducted in breast cancer [18], non-small cell lung cancer (NSCLC) [19], and salivary gland carcinomas [20] in which tumors exhibited reduced expression of NUMB. On the other hand, overexpression of NUMB was found in astrocytomas [21] and cervical squamous carcinoma cells [22], suggesting that NUMB also possesses oncogenic potential.…”

NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer

“…149 Loss of NUMB is associated with tumour aggressiveness and BRCA1 status in patients with breast cancer, 150 and poor prognosis in patients with salivary gland carcinomas. 151 …”