Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis. PPP1R14B was degraded mainly through the ubiquitin-proteasome pathway. RPS27A recruited deubiquitinase USP9X to deubiquitinate and stabilize PPP1R14B, resulting in overexpression of PPP1R14B in TNBC tissues. Gain- and loss-of-function assays demonstrated that PPP1R14B promoted TNBC cell proliferation, colony formation, migration, invasion, and resistance to paclitaxel in vitro. PPP1R14B also induced xenograft tumor growth, lung metastasis and paclitaxel resistance in vivo. Mechanistic investigations revealed that PPP1R14B maintained phosphorylation and stability of oncoprotein stathmin 1 (STMN1), a microtubule-destabilizing phosphoprotein critically involved in cancer progression and paclitaxel resistance, which was dependent on PP1 catalytic subunits α and γ. Importantly, the tumor suppressive effects of PPP1R14B deficiency could be partially rescued by ectopic expression of wild-type but not phosphorylation-deficient STMN1. Moreover, PPP1R14B increased STMN1-mediated α-tubulin acetylation, microtubule stability, and cell-cycle progression, leading to resistance of TNBC cells to paclitaxel. Collectively, these findings uncover a functional and mechanistic role of PPP1R14B in TNBC progression and paclitaxel resistance, indicating PPP1R14B is a potential therapeutic target for TNBC.

C9orf142 transcriptionally activates MTBP to drive progression and resistance to CDK4/6 inhibitor in triple‐negative breast cancer

“…After fixed with paraformaldehyde, the survival colonies clones were stained with crystal violet. Flow cytometry assay was used to determine cell cycle, following the previously described protocol 32 …”

“…For xenograft tumour experiments, cells were inoculated into the mammary fat pads of mice. Tumour size was measured every 2 days, and tumour volume was calculated using the method described previously 32 . To determine the effects of CDK4/6 inhibitor abemaciclib on xenograft tumour growth, phosphate buffered solution (PBS) or abemaciclib (25 mg/kg) was administered by oral gavage daily when the average tumour volumes reached 100 mm 3 .…”

Human basal-like breast cancer is represented by one of the two mammary tumor subtypes in dogs

“…Human breast cancer is heterogeneous, consisting of well-established molecularly distinct subtypes [1][2][3][4][5][6][7][8][9][10]. One of these subtypes is basal-like breast cancer (BLBC; human BLBC will be referred to as hBLBC hereafter), which makes up roughly 15-20% of human breast cancers and has the worst prognosis of all subtypes [1][2][3][4][5][6][7][8][9][10].…”

“…Human breast cancer is heterogeneous, consisting of well-established molecularly distinct subtypes [1][2][3][4][5][6][7][8][9][10]. One of these subtypes is basal-like breast cancer (BLBC; human BLBC will be referred to as hBLBC hereafter), which makes up roughly 15-20% of human breast cancers and has the worst prognosis of all subtypes [1][2][3][4][5][6][7][8][9][10]. About 70% of hBLBCs are triple negative, expressing neither estrogen receptor (ER) nor progesterone receptor (PR) and without HER2 amplification or overexpression [1][2][3][4][5][6][7][8][9][10].…”

“…These cancers also tend to have increased rates of cell proliferation and metastasis [1][2][3][4][5][6][7][8][9][10]. All these highlight the need for an effective translational model for hBLBC, which is critically missing at present [11][12][13].…”