Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Abstract

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.

Fisetin induces DNA double-strand break and interferes with the repair of radiation-induced damage to radiosensitize triple negative breast cancer cells

“…However, it inhibited AKT (S473) phosphorylation in MDA-MB-231, with relatively lower levels of AKT phosphorylation shown in Fig. S 1 and reported before [ 36 ]. In HSF-7 normal human fibroblast, fisetin slightly inhibited YB-1 (S102) phosphorylation only at concentrations of 25 and 50 µM (Fig.…”

Quantitative Proteomics Reveals Knockdown of CD44 Promotes Proliferation and Migration in Claudin-Low MDA-MB-231 and Hs 578T Breast Cancer Cell Lines

“…Previous studies have demonstrated that activation of the signaling pathway depends on the mutation status of cell lines. MDA-MB231 cells harbor KRAS­(G13D) and BRAF­(G464V) mutations that lead to the hyperactivation of the MAPK/ERK pathway in association with the suppression of Akt phosphorylation. − Hs 578T cells harbor an HRAS­(G12D) mutation that leads to the hyperactivation of both the PI3K/Akt and MAPK/ERK pathways . CD44 regulation affected distinct signaling pathways, indicating that even if it is expressed at a similar level in the two claudin-low breast cancer cell lines, its functions might depend on the difference in the genetic background and origin.…”

YB1 Is a Major Contributor to Health Disparities in Triple Negative Breast Cancer

“…The Y Box binding protein 1 (YB1) is a multifunctional protein, found both in the cytoplasm and inside the nucleus, that belongs to the highly conserved Cold Shock Domain protein family [ 16 ]. Among its multitude of functions, YB1 is more known to be involved in the regulation of transcription, mRNA stability, and splicing [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. More recently, YB1 was found to play key roles in the regulation of tumor development, progression and metastasis, as well as drug resistance in several cancers, including the ones generated in the breast [ 17 , 24 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

“…Among its multitude of functions, YB1 is more known to be involved in the regulation of transcription, mRNA stability, and splicing [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. More recently, YB1 was found to play key roles in the regulation of tumor development, progression and metastasis, as well as drug resistance in several cancers, including the ones generated in the breast [ 17 , 24 , 26 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. In this study, we show that dysregulated YB1 expression to be associated primarily with breast cancer cell lines in primary tumors of the TNBC subtype as compared to their luminal or HER2+ counterparts.…”