RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis

AbstractTransforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.

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Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver

10.1101/479568 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michiel Fokkelman ◽

Esmee Koedoot ◽

Vasiliki-Maria Rogkoti ◽

Sylvia E. Le Dévédec ◽

Iris van de Sandt ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Cancer Cell Migration ◽

Metastasis Formation ◽

Breast Cancer Cell Migration ◽

Basal Breast Cancer

AbstractMetastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.

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Arl13b Regulates Breast Cancer Cell Migration and Invasion by Controlling Integrin-Mediated Signaling

Cancers ◽

10.3390/cancers11101461 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1461 ◽

Cited By ~ 2

Author(s):

Cristina Casalou ◽

Alexandra Faustino ◽

Fernanda Silva ◽

Inês C. Ferreira ◽

Daniela Vaqueirinho ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Progression ◽

Migration And Invasion ◽

Breast Cancer Cell Lines ◽

Cancer Cell Migration ◽

Cell Migration And Invasion ◽

Breast Cancer Cell Migration

Breast cancer is the first cause of cancer-related mortality among women worldwide, according to the most recent estimates. This mortality is mainly caused by the tumors’ ability to form metastases. Cancer cell migration and invasion are essential for metastasis and rely on the interplay between actin cytoskeleton remodeling and cell adhesion. Therefore, understanding the mechanisms by which cancer cell invasion is controlled may provide new strategies to impair cancer progression. We investigated the role of the ADP-ribosylation factor (Arf)-like (Arl) protein Arl13b in breast cancer cell migration and invasion in vitro, using breast cancer cell lines and in vivo, using mouse orthotopic models. We show that Arl13b silencing inhibits breast cancer cell migration and invasion in vitro, as well as cancer progression in vivo. We also observed that Arl13b is upregulated in breast cancer cell lines and patient tissue samples. Moreover, we found that Arl13b localizes to focal adhesions (FAs) and interacts with β3-integrin. Upon Arl13b silencing, β3-integrin cell surface levels and FA size are increased and integrin-mediated signaling is inhibited. Therefore, we uncover a role for Arl13b in breast cancer cell migration and invasion and provide a new mechanism for how ARL13B can function as an oncogene, through the modulation of integrin-mediated signaling.

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Interleukin-1βAffects MDAMB231 Breast Cancer Cell Migration under Hypoxia: Role of HIF-1αand NFκB Transcription Factors

Mediators of Inflammation ◽

10.1155/2015/789414 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Irene Filippi ◽

Fabio Carraro ◽

Antonella Naldini

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Cancer Cell Migration ◽

Breast Cancer Cell Migration

Inflammation and tumor hypoxia are intimately linked and breast cancer provides a typical example of an inflammation-linked malignant disease. Indeed, breast cancer progression is actively supported by inflammatory components, including IL-1β, and by the hypoxia-inducible factor- (HIF-) 1α. In spite of many attempts where the role of either IL-1βor HIF-1αwas evaluated, detailed mechanisms for their effects on breast cancer cell migration under hypoxia are still unclear. We here report that IL-1βincreased MDAMB231 cell migration under hypoxic conditions along with HIF-1αaccumulation and upregulation of CXCR1, which is transcriptionally regulated by HIF-1α, as well as an increased expression of CXCL8 and NFκB. In addition, IL-1β-induced cell migration in hypoxia was not affected when HIF-1αwas inhibited by either siRNA or Topotecan, well known for its inhibitory effect on HIF-1α. Of interest, HIF-1αinhibition did not reduce NFκB and CXCL8 expression and the reduction of IL-1β-induced cell migration under hypoxia was achieved only by pharmacological inhibition of NFκB. Our findings indicate that inhibition of HIF-1αdoes not prevent the migratory program activated by IL-1βin hypoxic MDAMB231 cells. They also suggest a potential compensatory role of NFκB/CXCL8 pathway in IL-1β-induced MDAMB231 cell migration in a hypoxic microenvironment.

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