L1CAM is expressed in triple-negative breast cancers and is inversely correlated with Androgen receptor

Abstract

BackgroundBreast cancer is a heterogeneous disease displaying distinct molecular features and clinical outcome. The molecular profile of triple-negative breast cancers (TNBCs) overlaps with that of basal-like breast cancers that in turn show similarities with high-grade serous ovarian and endometrial carcinoma. L1CAM is an established biomarker for the latter cancers and we showed before that approximately 18% of primary breast cancers are positive for L1CAM and have a bad prognosis. Here we analysed the expression of L1CAM breast cancer subtypes.MethodsWe analyzed mRNA and protein expression data from different breast cancer cohorts for L1CAM, estrogen receptor, progesterone receptor, Her-2 and Androgen receptor (AR) and correlated the data. We performed Western blot analysis on tumor cell lysates and carried out chromatin-immuno-precipitation (CHIP) after AR overexpression.ResultsWe find that L1CAM is expressed preferentially though not exclusively in TNBCs. Using the human cancer genome atlas database and two independent breast cancer cohorts we find that L1CAM is inversely correlated with androgen receptor (AR) expression. We found that L1CAMhighARlow primary breast tumors have the worst clinical outcome. Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region.ConclusionsThese results suggest that L1CAM in breast cancer is under AR control. The data also strongly advocate the use of L1CAM assessment in breast cancer diagnosis. We suggest that L1CAM expression could be causally related to the bad prognosis of TNBCs.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-958) contains supplementary material, which is available to authorized users.

A Prominent Couple

“…Zhu et al showed that stimulation of fibroblasts with recombinant TGF-β results in a decreased expression of SMAD7 [54]. In agreement with previous reports in MCF-10A breast cancer cells [55], TGFB1 knockdown also decreased miR-503 expression. MiR-503-mediated repression of SMAD7 therefore appears to be a way to escape the inhibitory effect of SMAD7 on TGF-β and WNT/β-catenin signaling.…”

“…Among the analysed PCa cell lines, the L1CAM mRNA level was highest in the neuroendocrine NCI-H660 cells (Figure 4.9A). In human PCa samples of the ExonArray IGP cohort, L1CAM was negatively correlated to AR expression (Figure 4.9B), which is consistent with earlier reports [55]. In contrast, L1CAM further showed positive correlation with CHGA and SYP (Figure 4.9B) suggesting that it is upregulated when PCa cells lose their epithelial properties.…”

“…Gene body methylation has frequently been associated with increased mRNA transcription [55]. DNA methylation was proposed to be mechanistically facilitated by open and actively transcribed chromatin [56].…”

“…CRPC can initially be treated by blocking AR signaling activity with the second-generation AR antagonist enzalutamide, and androgen synthesis inhibitors such as abiraterone [49,50]. The development of CRPC is driven by the genomic instability of PCa cells and multiple me-chanisms lead to the aberrant reactivation of AR signaling, including receptor promiscuity allowing alternative ligand binding, AR gene amplification [51,52], recruitment of alternating transcriptional coregulators [53][54][55][56] and AR splice variants. C-terminal truncated splice variants constitutively drive AR signaling under castrate conditions [57,58].…”

Evaluating L1CAM expression in human endometrial cancer using qRT-PCR

“…In the context of EMT up-regulation of L1CAM has been reported to be induced by β-catenin and SLUG [9,16,17]. Down-regulation of L1CAM was found to be driven by the androgen receptor [18], neural restrictive silencer factor/ RE1 silencing transcription factor (NRSF/REST) [19] and PAX-2/8 [20]. Importantly, in endometrial carcinoma cell lines L1CAM has also been shown to be inhibited by DNA methylation of its promoter [21] and by various miRNAs whereby the most reliable data exist for miR-34a [22].…”