Tenascin-C expression in invasion border of early breast cancer: a predictor of local and distant recurrence

Abstract

Summary We have recently demonstrated an association between distant metastasis and the expression of the extracellular matrix glycoprotein tenascin-C (Tn-C) in the invasion border of small axillary node-negative breast carcinomas. Our purpose was to assess the relationship between the expression of Tn-C in the tumour invasion border and several histopathological and biological variables and to compare their usefulness in predicting local and distant disease recurrences. The original patient group consisted of 143 women with axillary node-negative breast cancer (one bilateral) treated with breast-conserving surgery and post-operative radiotherapy, and followed for a median of 8 years. Because of the small number of recurrences an additional group of 15 similarly treated women with recurrent breast cancer was also studied. The size of the tumour, its histology, including a possible intraductal component, and grade were re-evaluated. The expression of erbB-2, p53, Ki-67 and Tn-C was evaluated by immunohistochemistry. Ploidy and S-phase fraction (SPF) were assessed by flow cytometry. The only statistically significant prognostic factor for local recurrence was Tn-C expression in the invasion border. For metastasis Ki-67 positivity, tumour size and Tn-C expression in the invasion border were statistically significant, but Ki-67 positivity was the only independent prognostic factor. Tn-C expression in the invasion border was associated with a higher proliferation rate measured by Ki-67 and SPF, which is consistent with the suggested growth-promoting activity of Tn-C. Tn-C may be a useful marker in selecting patients for adjuvant therapies to reduce the rate of both local and distant cancer recurrences.

Involvement of Large Tenascin-C Splice Variants in Breast Cancer Progression

“…44 -46 Since comparisons of Tn-C expression and outcome of patients yielded conflicting results, the distribution and site of synthesis in breast cancer have been considered to have greater prognostic significance than its presence or absence. [12][13][14]47 Furthermore, although it has been evident for a long time that Tn-C has multiple variants produced by alternative splicing of its RNA, data on the distribution and biological functions of Tn-C variants in normal and diseased breast tissues has remained scarce. The lack of good monoclonal antibodies against Tn-C different variants, reactive in archived breast tissues, is partly to blame.…”

“…In addition, splice variants of these proteins, which are generally absent in normal adult tissues, become predominant. 4 -11 It has been reported that overexpression of Tn-C in breast cancer is related to a poor prognosis, and local and distant recurrence, [12][13][14] this being attributable to the ability to promote cell migration and proliferation demonstrated in vitro. 15,16 Tn-C is a hexameric glycoprotein, each subunit consisting of a TA (Tn assembly) domain; 14 ϩ 1/2 epidermal growth factor (EGF)-like domains, a variable number of fibronectin type III (FN III) repeats, and a C-terminal fibrinogen-related domain (FBG).…”

Tenascin C Induces Epithelial-Mesenchymal Transition–Like Change Accompanied by SRC Activation and Focal Adhesion Kinase Phosphorylation in Human Breast Cancer Cells

“…TNC expression in invasion border is reported to be a predictor of distant metastasis and local recurrence in breast cancer. 27,28 The environment of TNC-rich extracellular matrix in the cancer tissues could evoke reduced cell contacts, forming scattered and smaller cancer nests, and promote cell motility at invading fronts, accounting for the correlation of TNC positivity with poorer outcome of patients with breast cancers. TNC may, thus, be a key molecule responsible for malignant behavior of breast cancers, providing a target for future therapeutic approaches.…”

“…24,26 Furthermore, it is important to note that TNC expression is frequently observed in invasion borders of cancer tissues and in microinvasive foci around intraductal carcinomas, where cells may undergo EMT. 23,[27][28][29] TNC immunostaining in invasive fronts is correlated with higher risk of distant metastasis and local recurrence. 27,28 In mammary epithelial cell differentiation, TNC expression is inversely correlated with the polarized epithelial phenotype and the addition of TNC disturbs dome formation in vitro, indicating TNC interference with induction and maintenance of cytodifferentiation.…”

“…23,[27][28][29] TNC immunostaining in invasive fronts is correlated with higher risk of distant metastasis and local recurrence. 27,28 In mammary epithelial cell differentiation, TNC expression is inversely correlated with the polarized epithelial phenotype and the addition of TNC disturbs dome formation in vitro, indicating TNC interference with induction and maintenance of cytodifferentiation. 30 These observations support the hypothesis that TNC is an extracellular trigger of EMT in breast cancer progression, although there is still no direct evidence to confirm this.…”