Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas

Abstract

Background:Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15–20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers.Methods:Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation.Results:In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines.Conclusion:SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.

Expression of SOX10 in Salivary Gland Oncocytic Neoplasms: A Review and a Comparative Analysis with Other Immunohistochemical Markers

“…It is also a transcription factor usually expressed in acinar and intercalated ducts of normal major salivary glands, salivary gland tumors with myoepithelial and acinar differentiation as well as breast basal-like carcinomas [10,11]. A recently discovered staining property of SOX10 which may allow for a more precise classification of oncocytic salivary gland neoplasms consists of positive staining of salivary gland neoplasms with acinar differentiation such as AciCC [10,12].…”

Signaling Pathways in the Development of Infantile Hemangioma

“…activate an endogenous autoregulatory network in adult stem cells and reconstitute an entire mammary gland (Guo et al 2012). Meanwhile, showing stem cell characteristics such as self-renewal and multi-potency, Sox10 is one of the most studied Sox family genes, mainly because of their role in the survival of neural crest cells and compilation into neural-crest-derived melanocytes and glia (Cimino-Mathews et al 2013;Ivanov et al 2013). Invasive breast carcinomas, especially those with triple negative hormone expression and metastases seem to be supportive for myoepithelial differentiation (CiminoMathews et al 2013;Ivanov et al 2013).…”

“…Meanwhile, showing stem cell characteristics such as self-renewal and multi-potency, Sox10 is one of the most studied Sox family genes, mainly because of their role in the survival of neural crest cells and compilation into neural-crest-derived melanocytes and glia (Cimino-Mathews et al 2013;Ivanov et al 2013). Invasive breast carcinomas, especially those with triple negative hormone expression and metastases seem to be supportive for myoepithelial differentiation (CiminoMathews et al 2013;Ivanov et al 2013). Expression of Sox9, Sox10 and Slug was seen in 82-96% of the tumor cells prior to chemotherapy in our study, further supporting the fact that the transcription factors are highly active in the breast cancer tissue.…”

“…Recently Sox10 labeling has been documented in myoepithelial differentiated cells in salivary gland neoplasms and also in metaplastic triple negative breast cancers (Cimino-Mathews et al 2013;Ivanov et al 2013).…”

Sox10 expression in ovarian epithelial tumors is associated with poor overall survival

“…For example, in neuroendocrine tumors of the lung, it is expressed by sustentacular cells, the presence of which is inversely correlated with neuroendocrine tumor grade [13]. Sox10 expression has been reported in basal-like, triple-negative and metaplastic carcinoma of breast [14], acinic cell carcinoma, adenoid cystic carcinoma, myoepithelial carcinoma, pleomorphic adenoma of salivary gland [15,16], and hepatocellular carcinoma [17]. Sox10 reportedly functions as an oncogene by cell cycle dysregulation in melanomagenesis [18], and by activating the Wnt/β-catenin cascade in hepatocellular carcinoma [17].…”