Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

Roosmalen, Wies van; Dévédec, Sylvia E. Le; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, D.; Pont, Chantal; Graauw, Marjo de; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; Water, Bob van de

doi:10.1172/jci74440

Cited by 114 publications

(129 citation statements)

References 53 publications

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“…Many molecular pathways that promote cell proliferation, migration and invasiveness in cultured cells, have been shown to correlate with or contribute to tumor aggressiveness in vivo 45, 51 . We therefore focused our attention on genes that are upstream regulators of cell motility, which led us to the transcriptional repressor SNAI2 (also known as SLUG) a well-known promoter of cell motility and invasiveness in different normal and cancer cells 15 .…”

Section: Resultsmentioning

confidence: 99%

The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

Mendoza-Villanueva

Balamurugan

et al. 2016

Oncogene

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Hypoxia and inflammatory cytokines like interleukin-6 (IL6) are strongly linked to cancer progression, and signal in part through the transcription factor Ccaat/enhancer binding protein δ (C/EBPδ, CEBPD), which has been shown to promote mesenchymal features and malignant progression of glioblastoma. Here we report a different role for C/EBPδ in breast cancer. We found that the C/EBPδ protein is expressed in normal breast epithelial cells and in low-grade cancers. C/EBPδ protein (but not mRNA) expression correlates with estrogen receptor (ER+) and progesterone receptor (PGR) expression and longer progression-free survival of breast cancer patients. Specifically in ER+ breast cancers, CEBPD–but not the related CEBPB–mRNA in combination with IL6 correlated with lower risk of progression. Functional studies in cell lines showed that ERα promotes C/EBPδ expression at the level of protein stability by inhibition of the FBXW7 pathway. Furthermore, we found that C/EBPδ attenuates cell growth, motility and invasiveness by inhibiting expression of the SNAI2 (Slug) transcriptional repressor, which leads to expression of the cyclin dependent kinase inhibitor CDKN1A (p21CIP1/WAF1). These findings identify a molecular mechanism by which ERα signaling reduces the aggressiveness of cancer cells, and demonstrate that C/EBPδ can have different functions in different types of cancer. Furthermore, our results support a potentially beneficial role for the IL-6 pathway specifically in ER+ breast cancer and call for further evaluation of the role of intra-tumoral IL-6 expression and of which cancers might benefit from current attempts to target the IL-6 pathway as a therapeutic strategy.

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Section: Resultsmentioning

confidence: 99%

The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

Mendoza-Villanueva

Balamurugan

et al. 2016

Oncogene

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“…SRPK1 has also been suggested to be involved in ovarian cancer, hepatocellular carcinoma, non-small cell lung carcinoma and glioma [23][24][25][26][27] . Furthermore, immunohistochemistry staining of breast cancer tissue microarrays show that SRPK1 expression is linked to patient prognosis (our unpublished work, [22] ) and SRPK1 has recently been implicated in the regulation of breast cancer cell apoptosis, migration and metastasis [28] . Further analysis of large tissue patient datasets with follow up clinical information would enhance our understanding of the implications of SRPK1 and SRSF1 expression in prostate cancer.…”

Section: Introductionmentioning

confidence: 91%

Targeting the angiogenic 'splice' switch; inhibition of SRPK1 as a novel therapeutic approach in prostate cancer

Batson

Oltean

Bates

2015

Can Cell Microenviron

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Pathological angiogenesis occurs when the balance between pro-angiogenic and anti-angiogenic factors is tipped enabling an angiogenic switch. VEGF-A is the primary inducer of angiogenesis but is alternatively spliced at the pre-mRNA level to produce pro-angiogenic and anti-angiogenic isoforms. In previous work we showed that the balance of VEGF-A isoforms is regulated by SRSF1, which is regulated by phosphorylation from SRPK1 in renal epithelial cells, colon cancer cells, retinal epithelial cells and melanoma cells. SRPK1 and SRSF1 promote expression of pro-angiogenic VEGF-A165a and knockdown or inhibition of SRPK1 switches this balance towards anti-angiogenic VEGF-A165b, which inhibits angiogenesis and tumor growth in colon cancer and melanoma cells. In our recent study, Mavrou et al., 2014, we report that SRPK1 expression is upregulated in both prostatic intraepithelial neoplasia and malignant tissue sections from patients with radical prostatectomy. Knockdown or inhibition of SRPK1 with small molecule inhibitors leads to a splicing switch towards anti-angiogenic VEGF-A in PC-3 cells, a reduction in angiogenesis and inhibition of tumor growth in xenograft models. Specifically inhibiting pro-angiogenic VEGF-A splice isoforms through targeted inhibition of the splicing kinase SRPK1 is a novel approach which could enable development of therapies that are safer and more efficacious than current drugs. This study provides proof-of-concept for modulation of SRPK1 to normalise the endogenous VEGF-A splicing balance, enabling inhibition of angiogenesis and tumor growth in prostate cancer. Here, we discuss our recent findings and ongoing work to develop these findings into a novel therapeutic approach.

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“…In their recent study, van Roosmalen et al found that SRPK1 expression correlated with preferential metastasis of breast cancer to the lungs and brain. Subsequent SRPK1 knockdown appeared to suppress metastasis to distant organs, and to inhibit focal adhesion reorganization, suggesting that its activity and function are fundamental to tumour cell migration in this particular cancer type . Additionally, work published by Lin et al also suggests that SRPK1 may exert some of its tumourigenic effects in breast cancer through RNA‐binding motif protein 4‐mediated reduction in the expression of pro‐apoptotic IR‐B and MCL‐1 S transcripts, thereby modulating sensitivity to apoptotic signals .…”

Section: Srpk1 In Other Cancers: Mechanistic Differencesmentioning

confidence: 98%

“…Interestingly, although SRPK1 expression also appears to be increased in breast cancer [5], contemporary work seems to suggest an alternative mechanism of pathogenesis in this tumour type. In their recent study, van Roosmalen et al [13] found that SRPK1 expression correlated with preferential metastasis of breast cancer to the lungs and brain. Subsequent SRPK1 knockdown appeared to suppress metastasis to distant organs, and to inhibit focal adhesion reorganization, suggesting…”

Section: Srpk1 In Other Cancers: Mechanistic Differencesmentioning

confidence: 98%

The many faces of SRPK1

Bullock

Oltean

2017

The Journal of Pathology

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Serine–arginine protein kinase 1 (SRPK1) phosphorylates proteins involved in the regulation of several mRNA‐processing pathways, including alternative splicing. SRPK1 has been recently reported to be overexpressed in multiple cancers, including prostate cancer, breast cancer, lung cancer, and glioma. Several studies have shown that inhibition of SRPK1 has anti‐tumoural effects, and SRPK1 has therefore become a new candidate for targeted therapies. Interestingly, in terms of molecular mechanism, SRPK1 seems to act heterogeneously, and has been reported to affect several processes in different cancers, e.g. angiogenesis in prostate and colon cancer, apoptosis in breast and colon cancer, and migration in breast cancer. A recent report adds to this puzzle, showing that the main effect of SRPK1 overexpression in non‐small‐cell lung carcinoma is to stimulate a stem cell‐like phenotype. This pleiotropy might be related to preferential activation of different downstream signalling pathways by SRPK1 in various cancers. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

Cited by 114 publications

References 53 publications

The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

The C/EBPδ protein is stabilized by estrogen receptor α activity, inhibits SNAI2 expression and associates with good prognosis in breast cancer

Targeting the angiogenic 'splice' switch; inhibition of SRPK1 as a novel therapeutic approach in prostate cancer

The many faces of SRPK1

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