Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer

Egeland, Eivind Valen; Boye, Kjetil; Park, Daehoon; Synnestvedt, Marit; Sauer, Torill; Naume, Bjørn; Borgen, Elin; Mælandsmo, Gunhild M.

doi:10.1007/s10549-016-4096-1

Cited by 25 publications

(27 citation statements)

References 38 publications

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“…This is in line with previous studies demonstrating that basal‐like/TNBC, compared to luminal BC, have superior abilities to recruit macrophages (Espinoza et al ., 2016; Sousa et al ., 2015), modulate their polarization, and stimulate protumorigenic functions (Hollmen et al ., 2015; Sousa et al ., 2015; Stewart et al ., 2012; Su et al ., 2014). The current study adds to the previous knowledge by revealing a strong potentiating influence of S100A4, which is expressed at elevated levels in basal‐like/TNBC as also reported previously (Egeland et al ., 2017). Furthermore, TNBC shows elevated expression of TLR4 and RAGE receptors (Mehmeti et al ., 2015; Nasser et al ., 2015), which have been linked to S100A4‐trigged cytokine induction (Cerezo et al ., 2014; Haase‐Kohn et al ., 2011).…”

Section: Discussionmentioning

confidence: 99%

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

et al. 2018

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The tumor microenvironment (TME) may influence both cancer progression and therapeutic response. In breast cancer, particularly in the aggressive triple‐negative/basal‐like subgroup, patient outcome is strongly associated with the tumor's inflammatory profile. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells in the TME, shown to be linked to poor prognosis and therapeutic resistance. In this study, we investigated the effect of the metastasis‐ and inflammation‐associated microenvironmental factor S100A4 on breast cancer cells (BCCs) of different subtypes and explored their further interactions with myeloid cells. We demonstrated that extracellular S100A4 activates BCCs, particularly the basal‐like subtype, to elevate secretion of pro‐inflammatory cytokines. The secreted factors promoted conversion of monocytes to TAM‐like cells that exhibited protumorigenic activities: stimulated epithelial–mesenchymal transition, proliferation, chemoresistance, and motility in cancer cells. In conclusion, we have shown that extracellular S100A4 instigates a tumor‐supportive microenvironment, involving a network of cytokines and TAM‐like cells, which was particularly characteristic for basal‐like BCCs and potentiated their aggressive properties. The S100A4–BCC–TAM interaction cascade could be an important contributor to the aggressive behavior of this subtype and should be further explored for therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

et al. 2018

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“…Previous studies have not made a connection between the Daxx nuclear/cytoplasmic expression ratio and GC, and this is the first study of its type to use Daxx IHC in clinical gastric carcinoma tissue. Numerous previous studies have shown that protein subcellular localization can be closely related to tumor progression. In this study, we found that the subcellular localization of Daxx in cells is complex, because it is expressed in both the nucleus and the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that a protein's subcellular locations may be associated with different functions. In fact, numerous studies have shown that protein subcellular localization can be associated with functions that are closely related to tumor progression .…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of Daxx NCR (Nuclear/Cytoplasmic Ratio) in gastric cancer

Zhao

et al. 2017

Cancer Medicine

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In addition to regulating apoptosis via its interaction with the death domain of Fas receptor, death domain associated protein 6 (Daxx) is also known to be involved in transcriptional regulation, suggesting that the function of Daxx depends on its subcellular localization. In this study, we aimed to explore Daxx subcellular localization in gastric cancer (GC) cells and correlate the findings with clinical data in GC patients. Seventy pairs of tissue samples (GC and adjacent normal tissue) were analyzed immunohistochemically for Daxx expression and localization (nuclear and cytoplasmic). The Daxx Nuclear/Cytoplasmic ratio (Daxx NCR) values in tissue microarray data with 522 tumor samples were further analyzed. The defined Prior cohort (n = 277, treatment between 2006 and 2009) and Recent cohort (n = 245, treatment between 2010 and 2011) were then used to examine the relationship between Daxx NCR and clinical data. The Daxx NCR was found to be clinically informative and significantly higher in GC tissue. Using Daxx NCR (risk ratio = 2.0), both the Prior and Recent cohorts were divided into high‐ and low‐risk groups. Relative to the low‐risk group, the high‐risk patients had a shorter disease free survival (DFS) and overall survival (OS) in both cohorts. Importantly, postoperative chemotherapy was found having differential effect on high‐ and low‐risk patients. Such chemotherapy brought no survival benefit, (and could potentially be detrimental,) to high‐risk patients after surgery. Daxx NCR could be used as a prognosis factor in GC patients, and may help select the appropriate population to benefit from chemotherapy after surgery.

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“…S100A4 overexpression is closely related to the invasion and lymph node metastasis of colorectal and gastric cancer etc . For breast cancer, patients with S100A4‐positive tumors had inferior prognosis compared to S100A4‐negative, and S100A4 blocking antibody reduces tumor growth and metastasis in a model of breast cancer . S100A4 inhibition by RNAi suppresses the proliferation of gastric cancer cells in vitro and in vivo .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 For breast cancer, patients with S100A4-positive tumors had inferior prognosis compared to S100A4-negative, and S100A4 blocking antibody reduces tumor growth and metastasis in a model of breast cancer. 3,4 S100A4 inhibition by RNAi suppresses the proliferation of gastric cancer cells in vitro and in vivo. 5 The above results indicate that S100A4 plays important roles in the progression of many types of cancer, including gastric cancer.…”

Section: Introductionmentioning

confidence: 99%

IL‐1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem‐like properties through PI3K pathway

Wang

Bian

et al. 2018

J of Cellular Biochemistry

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It has been shown that nuclear expression of S100A4 is significantly correlated with increased metastasis and reduced survival in patients with gastric cancer and many other cancers. However, the factors which could influence the nuclear contents of S100A4 in cancer cells are not clear. It has also been reported that Interleukin-1β (IL-1β) promotes the nuclear translocation of S100A4 in chondrocytes. Previous studies have shown that IL-1β promotes the stemness of colon cancer cells, and S100A4 is also involved in maintaining cancer-initiating cells in head and neck cancers. We speculate that IL-1β might promote the nuclear translocation of S100A4 protein in MGC803 gastric cancer cells and therefore enhance their stem-like properties. The results from Western-blot and qRT-PCR analysis showed that IL-1β increased the nuclear and total cellular content of S100A4 protein and S100A4 mRNA level in MGC803 cells. LY294002, a pharmacological inhibitor of Phosphoinositide 3-kinase (PI3K) reversed the above effects. Functional studies indicated that IL-1β promoted the colony-forming and spheroid-forming capabilities of the cells and the expression of SOX2 and NANOG gene. PI3K or S100A4 inhibition reversed the IL-1β-mediated increase in colony and spheroid-forming capabilities of the cells. LY294002 also reversed the elevated SOX2 and NANOG expression induced by IL-1β. Our study demonstrated that IL-1β promote the nuclear translocation of S100A4 protein in gastric cancer cells MGC803, which are PI3K dependent, suggesting the existence of IL-1β-PI3K-S100A4 pathway for the first time. The study also showed that IL-1β promoted stem-like properties of the cells through the new pathway.

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Prognostic significance of S100A4-expression and subcellular localization in early-stage breast cancer

Cited by 25 publications

References 38 publications

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

Prognostic significance of Daxx NCR (Nuclear/Cytoplasmic Ratio) in gastric cancer

IL‐1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem‐like properties through PI3K pathway

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