Abstract
Simple SummaryTriple-negative breast cancer (TNBC) is associated with the high rates of relapse and metastasis and poor survival. YB-1 is overexpressed in TNBC tumor tissues. In the present study, we demonstrated that S102 phosphorylation of YB-1 in TNBC cell lines depend on the mutation status of the components of the MAPK/ERK and PI3K/Akt pathways. Simultaneous targeting of MEK and PI3K was found to be the most effective approach to block YB-1 phosphorylation and to inhibit YB-1 dependent cell proliferation. YBX1 knockout was sufficient to block TNBC tumor growth.The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.
Highlights
Y-box binding protein-1 (YB-1), encoded by the YBX1 gene, is a multifunctional protein that participates in DNA repair, gene transcription, mRNA splicing, and translation [1]
We investigated the level of phosphorylation of YB-1 (S102), phosphorylation of ERK1/2 (T202/Y204), and expression of EGFR in a limited number of tumor tissues from breast cancer patients, including those with triple-negative breast cancer (TNBC)
We showed that serine 102 (S102) phosphorylation of YB-1 in three TNBC cell lines depends on mutation status of the components of the MAPK/ERK and PI3K/Akt pathways
Summary
Y-box binding protein-1 (YB-1), encoded by the YBX1 gene, is a multifunctional protein that participates in DNA repair, gene transcription, mRNA splicing, and translation [1]. YB-1 is one of the rare proteins that regulates the cellular signaling pathways underlying nearly every cancer hallmark [2,3]. As both a cytoplasmic and nuclear protein, YB-1 is highly expressed in different cancer types, such as breast, lung, colorectal, melanocytic, prostate, ovary, and bone cancer [2,4,5,6,7]. Previous reports have demonstrated that signaling pathways downstream of ERK regulate YB-1 S102 phosphorylation [11,12,13]. Phosphorylation of nuclear YB-1 after various cellular stress, e.g., ligand stimulation, irradiation, and expression of KRAS(G12V), is regulated by nuclear translocation of phospho-RSK [16]. Targeting RSK could be an efficient approach for eliminating tumor-initiating cells via YB-1 inactivation in triple-negative breast cancer (TNBC) [15]
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