Fernando Martínez-Arribas

Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer

The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Immunohistochemical studies have shown that this overexpression is linked to higher aggressiveness of colorectal carcinoma and to enhanced metastatic potential of melanoma cells. However, the antibodies so far developed against Nup88 have the drawback of recognizing a number of other, up to now unspecified antigens besides Nup88. For this reason, we devised the present study on Nup88 expression at the mRNA level. RNA was extracted from fresh tumor tissue corresponding to 122 breast cancer patients. Nup88 mRNA expression was measured by means of differential RT‐PCR, standardizing against a constitutive internal control gene (β‐actin). The results were dichotomized into “high” and “low” expression levels, using the median value as cut‐off. High Nup88 mRNA expression levels correlated significantly with ductal and tubular histology (p = 0.012), histologic and nuclear grade 3 of tumors (p < 0.001), absence of hormone receptor expression (p < 0.001), expression of the c‐erb‐B2 oncogene (p < 0.001), expression of mutant p53 protein (p < 0.001), high proliferation (defined by Ki67 labeling index >20%, p < 0.001), DNA aneuploidy (p < 0.001) as well as the most important ominous clinical prognostic factor, axillary node invasion (p < 0.001). We also found an inverse correlation (p < 0.001) with expression of the H‐MAM (mammaglobin) gene, a marker of low biologic and clinical aggressiveness of breast cancer. All of these factors, without exception, define a highly aggressive tumor phenotype. These findings appear to be specific to Nup88 and not to nuclear pore proteins in general. Indeed, analysis of Nup107 (which is a limiting component of the nuclear pore complex) under the same conditions in the same tumors did not yield comparable results.

Positive correlation between the expression of X-chromosome RBM genes (RBMX, RBM3, RBM10) and the proapoptotic Bax gene in human breast cancer

In a recent report, it has been postulated that the ubiquitous RBM proteins might constitute a novel family of apoptosis modulators. We measured the expression of the X‐chromosome RBM genes (RBMX, RBM3, and RBM10) in 122 breast cancers by means of differential RT‐PCR. Using the same method, we also studied the expression of the apoptosis‐related genes Bcl‐2 and Bax. Markers of hormone dependence (estrogen and progesterone receptors), proliferation (Ki67 and DNA‐ploidy), angiogenesis (VEGF and CD105), as well as oncogene (c‐erb‐B2), and tumor suppressor gene (p53) expression were also analyzed. The expression of all X‐chromosome RBM genes was significantly associated with the expression of the proapoptotic Bax gene (RBMX, P = 0.039; RBM3, P < 0.001; RBM10 large variant, P < 0.001; RBM10 small variant, P < 0.001). Furthermore, the expression of both RBM10 variants was significantly associated with the expression of the VEGF gene (large variant, P = 0.004; small variant, P = 0.003). We also found an association of borderline significance (P = 0.05) between the expression of RBM3, the large variant of RBM10 and wild‐type p53. Expression of the small RBM10 variant, finally, was associated with high proliferation of the tumors (Ki67 ≥ 20%; P = 0.037). The expression of both RBM10 variants seems to be interdependent to a significant degree (r = 0.26, P = 0.006). From these results, it seems that the X‐chromosome, through its RBM genes, plays a formerly unknown role in the regulation of programmed cell death (apoptosis) in breast cancer. J. Cell. Biochem. 97: 1275–1282, 2006.

Nup88 expression is associated with myometrial invasion in endometrial carcinoma.

Background: The nuclear pore complex protein Nup88 has been shown in previous studies to be overexpressed in tumor cells and to be associated in breast cancer with all clinical and biological features defining a more aggressive phenotype. Methods: In this pilot study, Nup88-mRNA expression was studied in a series of 29 endometrial carcinomas, of which 27 belonged to the endometrioid variety, the remaining 2 being papillary serous tumors, to verify if Nup88 plays a similar role in endometrial carcinoma as the one described in breast cancer. The tumor samples were obtained directly at the operating suite and fresh frozen at the time of hysterectomy. Nup88-mRNA expression was studied in them by means of differential reverse transcriptase-polymerase chain reaction. Nup88-mRNA expression was correlated with the clinical features of the tumors. Results: A significant correlation (r = 0.41, P = 0.027) was found between growing levels of Nup88-mRNA expression and depth of myometrial invasion. There was no correlation between Nup88-mRNA expression and the other 2 available clinical parameters, that is, tumor grade (r = 0.05, P = 0.79) and surgical stage (r = −0.18, P = 0.34). Conclusions: From these results, it is concluded that Nup88 expression seems indeed to be associated with a distinct feature of tumor aggressiveness (myometrial invasion) in endometrial carcinoma and that larger studies are therefore probably worthwhile.