Relationship Between S100A4 S100A4v and nm23 Expression to Nodal Spread of Breast Cancer

Gene Expressed Relationship to Nodal Spread3

S100A4 +

S100A4+nm23 ++

S100A4v+b -

S100A4-/S100A4v-b +

a +, statistically significant relationship (p < .05); ++, strong relationship (p < .01).

b The expression of S100A4v (the splice variant form) alone did not relate to nodal spread; however, tumours that express neither S100A4 nor S100A4v do not tend to spread to the regional lymph nodes. Only 27% of carcinomas expressing neither h-mts1 nor h-mts1v showed metastatic spread to the lymph nodes; 57% (4/7) of carcinomas in which only the variant isoform was detectable showed nodal metastasis. This apparent difference did not reach statistical significance.

Source: Based on Albertazzi et al. (1998a, 1998b). Reprinted by permission of the publisher Mary Ann Liebert Inc.

The clinical data, together with the state of expression of steroid receptors and the expression levels of S100A4 and nm23 genes, were analysed using artificial neural networks (ANNs) for accuracy of prediction of nodal spread of the carcinomas. Naguib et al. (1997) previously had demonstrated that ANNs could be used to predict nodal involvement in breast cancer. In that study several established as well as experimental cancer markers had been analysed, and ANN techniques were found to be capable of dissecting and identifying the most powerful predictors of nodal metastasis. The ANN analyses, provided by Albertazzi et al. (1998b) as well as by Naguib et al. (1998), have also supported the conclusion that, overall, S100A4 expression is associated with and indicative of more aggressive forms of the disease. The investigation of Albertazzi et al. (1998b) does emphasise the view that when complemented with nm23, S100A4 could provide a powerful marker for predicting breast cancer prognosis. On the other hand, S100A4 might be a significant and independent marker for prognosis. An investigation of a large series of breast cancer over a period of 16 years has led Rudland et al. (2000) to conclude that S100A4 expression correlates strongly with patient survival. The Rudland group found S100A4 mRNA in both epithelial and stromal components of breast cancers and, further, that the levels of S100A4 are higher in carcinomas as compared with benign breast tumours (Nikitenko et al. 2000). They have also reported that 80% of patients who were S100A4 negative were alive after 19 years of follow-up, whereas only

11% of S100A4-positive patients were alive at the end of this period. The correlation between S100A4 negativity and survival was highly statistically significant.

Interestingly, Rudland et al. (2000) found that S100A4 expression correlated only marginally with axillary lymph nodal involvement. Nevertheless, S100A4-positive patients who were also node positive had poorer survival than S100A4 patients with no nodal involvement. The involvement of regional lymph nodes is regarded as the most consistent predictor of prognosis (Angus et al. 2000). The poorer prognosis of the S100A4+/node+ group may be related to whether or not S100A4 is expressed by tumour cells in the regional lymph nodes. Overall, the work reviewed here leaves little room for doubt that S100A4 is associated with tumour malignancy and prognosis. With the large body of evidence of the active participation of S100A4 in a wide spectrum of cellular functions, a demonstration of its association with metastatic cells of human breast cancer would be the coup de grace that is long awaited and that might satisfy the scientific cognocenti.

As stated previously, two splice variants of S100A4 have been reported so far (Ambartsumian et al. 1995; Albertazzi et al. 1998c). The larger variant, described by Ambartsumian et al. (1995), occurs in many tissues, although with differences in the levels of expression. Albertazzi et al. (1998c) found only the shorter splice variant (h-mts1v) in the series of breast cancers that they had investigated. They did not detect the expression of either variant in a number of tumour cell lines. The apparently highly specific nature of its expression is somewhat inexplicable. Nonetheless, Albertazzi et al. (1998c) found that h-mtsv expression did tend to correlate with nodal spread of breast cancers, albeit the correlation was not as persuasive as in the case of the unspliced S100A4 transcript.

Notwithstanding the positive nature of these findings, it ought to be stated here that assessing the state of expression of the S100A4 protein, not merely that of its mRNA, is equally important for providing a total picture of the relevance of the gene to progression of cancer. It is the occurrence of the functional protein that would determine the nature of the downstream events that define the degree of aggressiveness of the disease. As Ambartsumian et al. (1999) observed recently, S100A4 mRNA is expressed in all organs of S100A4 transgenic mice that they had developed. However, the protein is not expressed in organs that do not normally express the S100A4 gene in the wild-type animals. Therefore, it is imperative that information concerning the expression of the protein is collated at the same time as the mRNA levels are measured. This would take into account the fact that there may exist mechanisms that regulate the translation of the mRNA transcripts and possibly also decay of the protein in the normal course of cellular events.

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