SPOCK1 Is a Novel Transforming Growth Factor-β–Induced Myoepithelial Marker That Enhances Invasion and Correlates with Poor Prognosis in Breast Cancer

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.

Stromal SPOCK1 supports invasive pancreatic cancer growth

“…Previous publications have demonstrated a role for SPOCK1 in cancer types such as breast cancer (Fan et al ., ), prostate cancer (Chen et al ., ; Yang et al ., ), glioblastomas (Yu et al ., ), urothelial carcinomas (Ma et al ., ), ovarian cancer (Zhang et al ., ), esophageal squamous cell carcinomas (Song et al ., ), gallbladder cancer (Shu et al ., ), lung cancer (Miao et al ., ), and hepatocellular carcinomas (Li et al ., ). All these studies focused on the epithelial fraction.…”

“…SPOCK1 is a glycoprotein, highly similar to SPARC, a well-studied and characterized protein in the context of PDAC tumor growth (Hidalgo et al, 2015). Recently, the significance of SPOCK1 for tumor growth, apoptosis, epithelial-to-mesenchymal transition (EMT), and metastasis has been reported for tumor types other than PDAC (Fan et al, 2016;Li et al, 2013;Ma et al, 2016;Miao et al, 2013;Shu et al, 2015;Yang et al, 2016;Yu et al, 2016). In these tumors, SPOCK1 appears to predominately be expressed in the epithelial fraction.…”

A potential prognostic marker and therapeutic target: SPOCK1 promotes the proliferation, metastasis, and apoptosis of pancreatic ductal adenocarcinoma cells

“…SPOCK1 is an essential driver in several human cancers, [4][5][6][7][8][9][10][11] and some studies have shown that SPOCK1 is critical for DNA repair, cell cycle regulation, metastasis, and apoptosis. The oncogene sparc/ osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a member of the Ca 2+ -binding proteoglycan family.…”

“…The oncogene sparc/ osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a member of the Ca 2+ -binding proteoglycan family. SPOCK1 is an essential driver in several human cancers, [4][5][6][7][8][9][10][11] and some studies have shown that SPOCK1 is critical for DNA repair, cell cycle regulation, metastasis, and apoptosis. However, data showing the role of SPOCK1 role in pancreatic cancer tumorigenesis and progression are limited, and the mechanism underlying the differential expression of SPOCK1 is very unclear.…”

Phenotype-driven transitions in regulatory network structure

“…Module 10 was also enriched for Type I interferon response, which may be a result of the increased blood and lymphatic penetrance in normal female breast development. We found module 17 to be enriched for "negative regulation of cell-substrate adhesion" and contained SPOCK1 and NOTCH1, both known markers of invasion and breast cancer progression (102)(103)(104)(105). Finally, module 5 was enriched in transcriptional regulation factors, similar to the enrichment in chromatin remodeling found in the male breast network.…”