bims-merabr 2025-05-11 papers

Int J Mol Sci. 2025 Apr 10. pii: 3576. [Epub ahead of print]26(8):

Knockdown of BAP31 Suppresses Tumorigenesis and Stemness in Breast Cancer Cells via the Hippo Pathway.

Zhenzhen Hao, Bo Zhao, Fei An, Wanting Zhang, Xiaoshuang Zhu, Shihao Meng, Bing Wang.

The enhancement of stemness in cancer cells is correlated with the malignancy level in human cancers. B cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression; however, its specific role in breast cancer remains unclear. This study aimed to elucidate the biological function and molecular mechanisms of BAP31 in tumorigenesis and cancer stemness. Cancer stemness was assessed through tumor sphere formation and flow cytometry assays. Western blot analysis was employed to examine alterations in core stemness factors in BAP31 knockdown cell lines, in order to explore potential underlying mechanisms. Finally, we explored the role of BAP31 by developing xenograft models using nude mice in vivo. Our findings revealed that BAP31 expression was elevated in breast cancer cells, and its knockdown led to a decrease in both sphere formation and the CD44+CD24- population. Furthermore, the knockdown of BAP31 significantly diminished the expression of core stemness factors, such as Sox2 and c-Myc, in breast cancer cells in vitro. Consistently, the suppression of BAP31 markedly inhibited the tumorigenicity and stemness of breast cancer in vivo. The functional analysis further indicated that the knockdown of BAP31 diminishes stemness by activating the Hippo pathway kinase MST1 and inhibiting the transcription factor YAP. Notably, our study was the first to demonstrate that BAP31 interacts with PCMT1, a direct negative regulator of MST1 kinase. These findings identify BAP31 as a regulator of the Hippo pathway, highlighting its critical role in breast cancer tumorigenesis and stemness. Consequently, BAP31 emerges as a potential therapeutic target for this malignancy.

Keywords: BAP31; MST1; PCMT1; stemness; tumorigenesis

DOI: https://doi.org/10.3390/ijms26083576

PLoS One. 2025 ;20(5): e0321889

DNMT3A facilitates breast cancer progression via regulating ADAMTS8 mediated EGFR-MEK-ERK activation.

Shan Yang, Meng Cheng, Shaonan Zhang, Haoqi Wang, Jiaxing Wang, Xi Zhang, Yunzhe Mi, Sainan Li.

ADAMTS8 inactivation by epigenetic modifications has been reported in various tumors, and the dysregulation of ADAMTS8 expression is associated with poor clinical outcomes, cancer cell invasion, and metastasis. De novo methylation, involving DNMT3A, plays an important role in cancer development; however, it remains unclear whether DNMT3A regulates the progressive expression of breast cancer by regulating ADAMTS8. Through published cancer-related datasets and clinical validation, we found that ADAMTS8 and DNMT3A expression negatively correlated in breast cancer, and both associated with patient prognosis. Related cell experiments have shown that DNMT3A overexpression promotes breast cancer cell proliferation, migration, invasion, and apoptosis, whereas silencing DNMT3A has the opposite effect. Through Co-IP experiments, we confirmed that DNMT3A binds directly to ADAMTS8. Methylation-specific PCR (MSP) experiments confirmed that DNMT3A mediates ADAMTS8 promoter methylation in breast cancer. In addition, DNMT3A activated the EGFR-MEK-ERK signaling pathway by effectively downregulating ADAMTS8, whereas silencing ADAMTS8 effectively inhibited this signaling pathway. Taken together, our findings suggest that DNMT3A activates the EGFR-MEK-ERK signaling pathway by silencing ADAMTS8 transcription through methylation, thereby promoting breast cancer development. Therefore, DNMT3A may serve as an inhibitory target in breast cancer-targeted therapy.

DOI: https://doi.org/10.1371/journal.pone.0321889

FASEB J. 2025 May 15. 39(9): e70557

Beige Adipocytes Promote Triple-Negative Breast Cancer Cell Migration and Malignancy Through BMP4 Signaling.

Ying-Fang Chen, Chung-Lin Jiang, Chi-Ling Tan, Pei-Hsiang Lai, Fu-Jung Lin.

Breast cancer remains a leading cause of cancer-related mortality among women, with adipocyte-breast cancer interactions playing a critical role in cancer progression. Mammary gland fat contains both white and brown-like adipocytes. While white adipocytes have been associated with aggressive tumor behavior, the impact of brown-like adipocytes on cancer progression remains largely unclear. This study investigated the roles of beige (UCP1high) and white (UCP1low) adipocytes derived from human adipose-derived mesenchymal stem cells within the tumor microenvironment. Triple-negative breast cancer (TNBC) MDA-MB-231 cells exhibited increased migration and invasion when exposed to white (hWCM) or beige (hBCM) adipocyte-conditioned medium, with a more pronounced effect observed with hBCM. Mechanistically, beige adipocytes secreted significantly higher levels of bone morphogenetic protein 4 (BMP4) compared to white adipocytes, which enhanced TNBC cell migration. Inhibition of BMP signaling with Noggin effectively reduced the migration and malignancy of MDA-MB-231 cells induced by hBCM, underscoring the pivotal role of BMP4 in breast cancer progression. Furthermore, an ex vivo model using primary mature adipocytes revealed that co-culturing MDA-MB-231 cells with UCP1high adipocytes from cold-exposed mice increased cell migration and altered epithelial-mesenchymal transition gene expression compared to UCP1low adipocytes from room temperature-housed mice. These findings highlight the critical role of UCP1high beige adipocytes and BMP4 signaling in TNBC progression, suggesting that targeting BMP4 signaling may offer a novel therapeutic strategy for managing TNBC.

Keywords: BMP4; TNBC; beige adipocyte; breast cancer; tumor microenvironment

DOI: https://doi.org/10.1096/fj.202500158R

J Steroid Biochem Mol Biol. 2025 May 04. pii: S0960-0760(25)00098-6. [Epub ahead of print] 106770

G protein-coupled estrogen receptor reduces the breast cancer cell survival by regulating the IRE1α/miR-17-5p/ TXNIP pathway.

Maryam Mohammad-Sadeghipour, Mohammad Hadi Nematollahi, Maryam Sahebazzamani, Hassan Ahmadinia, Mohammad Reza Hajizadeh, Mehdi Mahmoodi, Amirhossein Sahebkar.

This study aimed to explore whether GPER can induce the UPR response in the SKBR3 cell line through ER and IREα activation, and to assess whether this response leads to cell survival or cell death. Additionally, the study sought to evaluate the impact of this response on cell behaviors such as apoptosis, migration, and drug resistance. To activate the UPR and induce ER stress, we treated the MCF10A cell line with 0.5µg/ml TUN for 24 and 48hours. The expression levels of XBP-1 and C/EBP homology protein (CHOP) genes (ER stress markers) were measured using the qRT-PCR technique. The MCF10A + TUN cell line was used as a positive control. To determine the optimal doses of G1 and tamoxifen (TAM), we evaluated GPER expression using qRT-PCR analysis. Cells were then treated with various doses of G1 (1000nM), G15 (1000nM), and TAM (2000 nM), both individually and in combination (G1 + G15, TAM + G15, G1 + TAM), for 24 and 48hours. We measured the expression of GPER, IRE1α, miR-17-5p, TXNIP, ABCB1, and ABCC1 genes. Apoptosis was assessed via flow cytometry, and cell migration was examined using the wound-healing assay. Our results demonstrated that GPER activation by G1 and TAM significantly increased IRE1α expression in SKBR3 cells. This activation, through its RIDD activity, cleaved miR-17-5p and initiated the UPR death response. The upregulation of the TXNIP gene expression enhanced apoptosis and chemotherapy sensitivity while decreasing cell migration. Interestingly, these effects were notably reversed by G15 treatment. In summary, the GPER/IRE1α/miR-17-5p/TXNIP axis plays a key role in the UPR pro-death response, promoting programmed cell death, reducing migration, and decreasing drug resistance in SKBR3 cells.

Keywords: Breast cancer; Drug resistance; G protein-coupled estrogen receptor; Inositol-Requiring Enzyme 1; Thioredoxin interacting protein; Unfolded protein response; miR-17-5p

DOI: https://doi.org/10.1016/j.jsbmb.2025.106770