11q24.3

Various cancers

ADAMTS-15 has recently emerged as a putative tumor suppresor gene since it is downregulated in breast cancer, and functionally inactivated through specific mutations in colorectal cancer (Porter et al., 2006; López-Otín et al., 2009; Viloria et al., 2009). In addition, aberrant expression of ADAMTS-15 is implicated in prostate cancer progression (Cross et al., 2005; Molokwu et al., 2010). The first indication regarding a potential protective role for ADAMTS15 derived from the observation that low ADAMTS15 expression levels coupled to high ADAMTS8 levels conferred poor prognosis to breast cancer patients (Porter et al., 2006). Moreover, ADAMTS15 was identified as one of the so-called CAN genes found to be mutated in a small set of colorectal cancers (Sjöblom et al., 2006). Functional support to the putative relevance of ADAMTS-15 as a tumor suppresor protease was described after finding four additional mutations in ADAMTS-15 gene sequence in human colon carcinomas (Viloria et al., 2009). Two of the new mutations resulted in the generation of truncated forms of ADAMTS-15, one of them lacking the last two thrombospondin domains whereas the other originating a complete ADAMTS-15 knock-down. Functional analysis revealed that the presence of the two last thrombospondin domains is important for the pericellular loacalization of ADAMTS-15 and affects the anti-tumoral function of full length ADAMTS-15 (Viloria et al., 2009; Dancevic et al., 2013). More recently, ADAMTS-15 has been described as a head and neck squamous cell carcinoma (HNSCC)-associated proteinase since its expression is elevated (together with ADAMTS-1 and ADAMTS-8) in areas surrounding HNSCC tumor microenvironment (Demircan et al., 2009; Stokes et al., 2010). In addition, these three members of the ADAMTS family have elevated expression levels in HNSCC tumor versus normal tissue and in HNSCC derived cell lines vs normal keratinocytes (Stokes et al., 2010). ADAMTS-15 has also been indirectly involved in androgen-mediated prostate cancer growth and proliferation, function that depends on ADAMTS-15 versicanolytic activity (Cross et al., 2005; Molokwu et al., 2010). Molokwu et al identified one androgen-responsive element (ARE) in ADAMTS-15 promoter and 12 more AREs in its gene sequence. In the same article the authors demonstrated ADAMTS-15 reduction both, at mRNA and protein levels, in the presence of dihidrotestorone (DHT). ADAMTS-15 down-regulation in prostate cancer resulted in high versican levels which is a poor prognosis indicator in these type of tumors (Ricciardelli et al., 1998; Luo et al., 2002; Molokwu et al., 2010).

Colon cancer

ADAMTS15 expression inversely correlates with histopathologic differentiation grade in human colorectal carcinomas when analyzing ADAMTS-15 inmunostaining in normal colon epithelia, well-differentiated tumors, moderately differentiated tumors, and poorly differentiated colorectal carcinomas (Viloria et al., 2009).

Head and neck squamous carcinoma (HNSCC)

ADAMTS15 mRNA levels, together with those of other ADAMTS members (ADAMTS1, ADAMTS4, ADAMTS5, ADAMTS8, ADAMTS9), were reduced in HNSCC primary tumors compared with paired non-cancerous tissues (Demircan et al., 2009). Regarding tumor microenvironment ADAMTS15 expression is elevated in adjacent and margin tissue when compared with tumor center tissue (Stokes et al., 2010).

Breast cancer

ADAMTS15 elevated expression correlates with favorable outcome in patients with breast cancer (Porter et al., 2006).