# Bisphosphate nucleotidase 1 promotes progression and docetaxel resistance in triple-negative breast cancer via STUB1-mediated destabilization of LIMA1

## TL;DR

This study identifies BPNT1 as a key driver of aggressive breast cancer and chemotherapy resistance, offering a new potential treatment target.

## Contribution

The paper reveals a novel BPNT1-STUB1-LIMA1 pathway involved in TNBC progression and drug resistance.

## Key findings

- BPNT1 promotes TNBC cell growth, migration, and metastasis in mice.
- BPNT1 induces LIMA1 degradation via STUB1, driving epithelial-mesenchymal transition.
- Reducing BPNT1 improves docetaxel sensitivity in TNBC cells.

## Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer without effective targeted therapies. Integrative analysis of transcriptomic and proteomic datasets of TNBC in our center revealed that bisphosphate nucleotidase 1 (BPNT1), a member of inositol monophosphatase superfamily with poorly characterized functional and mechanistic roles in human cancer, was abnormally upregulated in TNBC and its high expression was associated with poor patient prognosis. Loss- and gain-of-function assays revealed that BPNT1 acted as a novel oncogenic driver to promote TNBC cell proliferation, migration, invasion in vitro and to accelerate xenograft tumor growth and lung metastasis in mice. Mechanistically, BPNT1 recruited E3 ubiquitin ligase STUB1 (STIP1 homology and U-box containing protein 1) to induce proteasomal degradation of tumor suppressor protein LIMA1 (LIM domain and actin binding 1), thus promoting the epithelial-mesenchymal transition process and TNBC progression. Notably, re-expression of LIMA1 in BPNT1-overexpressing cells partially attenuated BPNT1-driven EMT and malignant phenotypes of TNBC cells. Furthermore, knockdown of BPNT1 enhanced the sensitivity of TNBC cells to the chemotherapeutic agent docetaxel. Collectively, these findings uncover a previously unknown role of the BPNT1-STUB1-LIMA1 axis in progression and docetaxel resistance in TNBC, and highlight BPNT1 as a potential therapeutic target for patients with TNBC.