Abstract
Dickkopf 3 (DKK3) has been associated with tumor suppression of various tumor entities including breast cancer. However, the functional impact of DKK3 on the tumorigenesis of distinct molecular breast cancer subtypes has not been considered so far. Therefore, we initiated a study analyzing the subtype-specific DKK3 expression pattern as well as its prognostic and functional impact with respect to breast cancer subtypes. Based on three independent tissue cohorts including one in silico dataset (n = 30, n = 463 and n = 791) we observed a clear down-regulation of DKK3 expression in breast cancer samples compared to healthy breast tissue controls on mRNA and protein level. Interestingly, most abundant reduction of DKK3 expression was detected in the highly aggressive basal breast cancer subtype. Analyzing a large in silico dataset comprising 3,554 cases showed that low DKK3 mRNA expression was significantly associated with reduced recurrence free survival (RFS) of luminal and basal-like breast cancer cases. Functionally, DKK3 re-expression in human breast cancer cell lines led to suppression of cell growth possibly mediated by up-regulation of apoptosis in basal-like but not in luminal-like breast cancer cell lines. Moreover, ectopic DKK3 expression in mesenchymal basal breast cancer cells resulted in partial restoration of epithelial cell morphology which was molecularly supported by higher expression of epithelial markers like E-Cadherin and down-regulation of mesenchymal markers such as Snail 1. Hence, we provide evidence that down-regulation of DKK3 especially promotes tumorigenesis of the aggressive basal breast cancer subtype. Further studies decoding the underlying molecular mechanisms of DKK3-mediated effects may help to identify novel targeted therapies for this clinically highly relevant breast cancer subtype.
Highlights
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among females worldwide [1]
Compared to the expression in normal breast tissue samples, triplenegative breast cancer” (TNBC) cases revealed a significantly reduced Dickkopf 3 (DKK3) expression (median fold change (FC): 12.7, P < 0.001), while expression loss was less abundant in carcinomas of the human epidermal growth factor receptor 2 (HER2)-positive and luminal subtype
The most abundant reduction of DKK3 expression was found in TNBC cases
Summary
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among females worldwide [1]. The clinical outcomes differ between the distinct biological breast cancer subtypes [2]. While luminal A breast carcinomas are associated with good prognosis, breast tumors of luminal B, HER2-enriched and basal-like subtypes are related to unfavorable clinical outcomes [4, 7]. Treatment of basal/triple negative tumors lacks in alternatives to chemotherapy underlining the urgent need to develop novel targeted, less toxic therapies for this breast cancer subtype [8]. To achieve this goal, further understanding of molecular alterations underlying the subtype-specific carcinogenesis is required
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