Abstract
In addition to contraction, myoepithelia have diverse paracrine effects, including a tumor suppression effect. However, certain myoepithelial markers have been shown to contribute to tumor progression. Transforming growth factor-β (TGF-β) is involved in the transdifferentiation of fibroblasts to contractile myofibroblasts. We investigated whether TGF-β can upregulate potential myoepithelial markers, which may have functional and clinicopathological significance in breast cancer. We found that TGF-β induced SPOCK1 expression in MCF10A, MCF12A, and M10 breast cells and demonstrated SPOCK1 as a novel myoepithelial marker that was immunolocalized within or beneath myoepithelia lining ductolobular units. A functional study showed that overexpression of SPOCK1 enhanced invasiveness in mammary immortalized and cancer cells. To further determine the biological significance of SPOCK1 in breast cancer, we investigated the expression of SPOCK1 in 478 invasive ductal carcinoma (IDC) cases through immunohistochemistry and correlated the expression with clinicopathological characteristics. SPOCK1 expression was significantly correlated with high pathological tumor size (P = 0.012), high histological grade (P = 0.013), the triple-negative phenotype (P = 0.022), and the basal-like phenotype (P = 0.026) and was correlated with a significantly poorer overall survival on univariate analysis (P = 0.001, log-rank test). Multivariate Cox regression analysis demonstrated that SPOCK1 expression maintained an independent poor prognostic factor of overall survival. Analysis of SPOCK1 expression on various non-IDC carcinoma subtypes showed an enrichment of SPOCK1 expression in metaplastic carcinoma, which is pathogenetically closely related to epithelial-mesenchymal transition (EMT). In conclusion, we identified SPOCK1 as a novel TGF-β–induced myoepithelial marker and further demonstrated that SPOCK1 enhanced invasion in breast cancer cells and correlated with poor prognosis in breast cancer clinical samples. The enrichment of SPOCK1 expression in metaplastic carcinoma and the correlation between SPOCK1 expression and high histological grading and basal-like phenotypes in IDC evidence an association between SPOCK1 and EMT.
Highlights
The mammary epithelium is composed of 2 cell layers, the inner luminal cells and the outer myoepithelial cells (MECs)
Among the 9 genes evaluated—namely POSTN, CXCR7, IGFL2, SPOCK1, PCDH9, PRRX2, FBN1, PLAT, and NOV—we found that SPOCK1 (SPARC/osteonectin, CWCV and kazal-like domains proteoglycan 1) was the only myoepithelial marker that was immunolocalized within or beneath the MECs (Fig 1A)
The SPARC family of proteins consists of SPARC, Hevin (SPARC-like protein 1), secreted modular calcium binding protein (SMOC) 1 and 2, testican-1, 2 and 3, and follistatin like protein 1 [18]
Summary
The mammary epithelium is composed of 2 cell layers, the inner luminal cells and the outer myoepithelial cells (MECs). A subset of breast tumors expressing MEC markers (e.g., CK5, caveolin 2, and secreted protein, acidic, cysteine-rich (SPARC)) are characterized by a poor clinical outcome [5,6,7]. This indicates that certain MEC markers may have tumor progressive effects and correlate with poorer prognosis. Identification of such MEC markers may contribute to the understanding of MEC marker-related mammary pathogenesis
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