Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype, representing about 10–15% of all malignant breast tumours [1]. It is characterized by the negativity for the expression of estrogen receptors (ER), progesterone receptors (PR), and the human epidermal growth factor receptor 2 (HER2) [2], [3]. Metaplastic breast cancer (MpBC) is a rare histologic variant of invasive BC, accounting for approximately 0.2–1% of all cases, of which the vast majority are TNBC [4], [5]. It involves tumours in which epithelial adenocarcinoma co-exists with an admixture of sarcomatous elements like spindle cell, chondroid or bone-forming malignant cells [6]. TN-MpBC patients have almost double the risk of relapse and shorter survival parameters compared to their TN-invasive ductal carcinoma (TN-IDC) counterparts, with estimated median survival of 8 months for metastatic patients [7]. Although both groups exhibit a TN phenotype, the poorer survival outcome for TN-MpBC is mostly due to its unique histogenesis and molecular drivers, that render it extremely resistant to the standard chemotherapy protocols used for TN-IDC patients with ultimately very low pathologic response rates [8], [9].

Syndecan-1 (SDC1/CD138), one of the four members of SDC family, is ubiquitously expressed on normal epithelial tissues [10]. Its dysregulated expression on tumour cells and stroma has been reported in different tumour types including BC [11]. Being a (co)receptor for a wide range of ligands, such as growth factors, cytokines, chemokines, extracellular matrix (ECM) proteins and integrins, SDC1 not only modulates cancer cell behaviour (e.g., proliferation, adhesion, migration, invasion, metastasis, angiogenesis, and cancer stem cell phenotype), but also regulates the crosstalk with stromal cells [12], [13], [14], [15]. Moreover, it is a critical modulator of multiple signalling events known to be activated in MpBC, such as epidermal growth factor receptor (EGFR) [11], [16], phosphoinositide 3-kinase (PI3K) [17], [18], and Wnt/β-catenin [19], [20]. Previous studies have examined the prognostic relevance of SDC1 expression in BC [21], [22], [23], [24], [25]. Of note, its cellular compartments (epithelial membranous, cytoplasmic and stromal) showed a differential impact on the prognosis of BC [21], [24]. At the functional level, we have previously demonstrated a link between SDC1 and a cancer stem cell phenotype, characterised by high developmental plasticity and therapeutic resistance [11], [19], these features were previously described to play a role in MpBC pathogenesis by Hennessy et al. [25].

Consequently, there is a persistent need to identify new biomarkers for MpBC, not only for prognostic significance, but also for the potential therapeutic benefit to overcome the well-known resistance to conventional chemotherapy regimens. Since the expression pattern and prognostic value of SDC1 in MpBC has not yet been fully elucidated, herein, we present our study to explore the prognostic impact of different compartmental SDC1 expression in TN-MpBC patients.