bims-merabr 2024-12-08 papers

Sci Rep. 2024 12 02. 14(1): 29950

WWP1 targeting PTEN for polyubiquitination to promote bone metastasis of luminal breast cancer.

Hao Jiang, Zhenxi Li, Wei Xu, Jianru Xiao.

Luminal breast cancer exhibits a high incidence of bone recurrence when metastasizing to distant organs. The mechanisms underlying the organotropism of luminal breast cancer cells remain unclear. In this study, we aimed to determine the role of WWP1 (WW domain-containing E3 ubiquitin protein ligase 1)-PTEN (phosphatase and tensin homolog deleted on chromosome ten) interaction in bone tropism in luminal breast cancer. We observed that WWP1 was overexpressed in luminal breast cancer tissues and associated with poor prognosis in breast cancer patients. In luminal breast cancer cells, WWP1 was found to mediate PTEN ubiquitination, resulting in the functional loss of PTEN. As a result, we demonstrate that WWP1 contributes to bone tropism in luminal breast cancer cells via the polyubiquitination of PTEN. Consequently, WWP1-mediated PTEN polyubiquitination contributed to the early metastasis of luminal breast cancer cells to the bone. Thus, our study provides a mechanistic insight into the bone tropism of luminal breast cancer cells and proposes a potential therapeutic strategy for mitigating cancer metastasis to the bone.

Keywords: Bone metastasis; Luminal breast cancer; PTEN; Ubiquitination; WWP1

DOI: https://doi.org/10.1038/s41598-024-81541-5

Front Oncol. 2024 ;14 1452981

Insulin-like growth factor-binding protein-3 is induced by tamoxifen and fulvestrant and modulates fulvestrant response in breast cancer cells.

Keenan L Flynn, Yan Zheng, Janel Y Sowers, Nefretiri J T Masangya, Kevin D Houston.

Introduction: Insulin-like growth factor binding protein-3 (IGFBP-3) exerts varying effects on estrogen receptor alpha (ERα)-positive and triple-negative breast cancer (TNBC) cells. In ERα-positive cells, IGFBP-3 is antiproliferative and proapoptotic. In contrast, IGFBP-3 stimulates proliferation in triple-negative breast cancer (TNBC) cells via EGFR activation.
Methods: To identify potential mechanisms that underlie the opposing effects of IGFBP-3 on these two breast cancer subtypes, IGFBP-3 expression was determined in cell line models of both ERα-positive breast cancer and TNBC, and cells were treated with antiestrogens tamoxifen and fulvestrant.
Results and discussion: MCF-7 and T-47D cells expressed low levels of IGFBP-3 when compared to MDA-MB-231 and MDA-MB-468 cells. MCF-7 cells with acquired resistance to the selective estrogen receptor degrader fulvestrant expressed high IGFBP-3 and MCF-7 cells with constitutive IGFBP-3 expression were fulvestrant resistant. IGFBP-3 expression was increased in all cell lines upon treatment with fulvestrant or the selective estrogen receptor modulator tamoxifen and both fulvestrant and tamoxifen increased TNBC cell proliferation. Further, IGFBP-3 expression was increased by treatment with the GPER1 agonist G-1 and attenuated upon treatment with P17, a YAP/TAZ inhibitor. These data suggest that IGFBP-3 modulates breast cancer cells and is a mediator of breast cancer cell response to fulvestrant and tamoxifen.

Keywords: GPER1; IGFBP-3; Yap/Taz; fulvestrant; insulin like growth factor binding protein; triple negative breast cancer

DOI: https://doi.org/10.3389/fonc.2024.1452981

J Biochem Mol Toxicol. 2024 Dec;38(12): e70074

Zingerone Facilitates Apoptosis in Triple Negative Breast Cancer Cells by Inducing Autophagy.

Xia Cao, Chien-Wei Chen, Kai Yin, Tzong-Luen Wang, Yao-Kuang Huang, Pang-Yen Chen, Po-Hua Su.

Triple negative breast cancer (TNBC) is characterized by high heterogenicity and aggressiveness and autophagy plays a complicated role in cancer development. Zingerone is reported to possess multiple pharmacological activities, including antitumors. This study explored the biological role and the relevant mechanisms of zingerone in TNBC. Following zingerone treatment, the viability of normal breast cancer cells MCF-10A and TNBC cells (MDA-MB-231 and MDA-MB-468) was detected with CCK-8 assay. The proliferation, migration and invasion of TNBC cells were detected with colony formation, wound healing, and transwell assays. Western blot was used to detect the expressions of migration-, apoptosis- and autophagy-related proteins. Flow cytometry was used to detect the cell apoptotic level and immunofluorescence assay measured the autophagy. The experimental data revealed that zingerone with varying concentrations suppressed cell viability, proliferation, migration and invasion while promoting the apoptosis in TNBC, which might be mediated by autophagy activation. Besides, zingerone decreased HDAC1 expression in TNBC cells and regulated autophagy via HDAC1. Collectively, zingerone impeded the malignant progression of TNBC via inducing HDAC1-mediated autophagy.

Keywords: HDAC1; apoptosis; autophagy; triple negative breast cancer; zingerone

DOI: https://doi.org/10.1002/jbt.70074

Oncogene. 2024 Dec 04.

Breast cancer stem cell-derived exosomal lnc-PDGFD induces fibroblast-niche formation and promotes lung metastasis.

Tingting Tang, Tao Yang, Huijie Xue, Xiao Liu, Jie Yu, Chen Liang, Dameng Li, Chenxi Xiang, Junnian Zheng, Liang Wei, Bo Ma.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastatic potential and lack of therapeutic targets. Breast cancer stem cells (BCSCs) are enriched in TNBC and contribute to its metastatic propensity. Accumulating evidence suggests that cancer-derived exosomes are key drivers of premetastatic niche formation in distal organs. However, the function and underlying mechanism of BCSC-derived exosomes in TNBC metastasis remain elusive. Here, we demonstrated that BCSC-derived exosomes exhibit a greater capacity to activate fibroblasts and promote TNBC cell metastasis to the lung than non-BCSC-derived exosomes. Additionally, we found that upregulation of exosomal long non-coding RNA platelet derived growth factor D (lnc-PDGFD) expression in BCSCs is responsible for fibroblast activation through YBX1/NF-kB signaling in the lung. Activated fibroblasts further promote tumor progression by secreting IL-11. Taken together, BCSC-derived exosomes enriched with lnc-PDGFD could activate fibroblasts, thereby facilitating lung metastasis in TNBC patients. These results provide new insights into the mechanism of TNBC metastasis to the lung.

DOI: https://doi.org/10.1038/s41388-024-03237-4

Cancer Drug Resist. 2024 ;7 48

Breast cancer cell resistance to hormonal and targeted therapeutics is correlated with the inactivation of the NR6A1 axis.

Olga E Andreeva, Danila V Sorokin, Svetlana V Vinokurova, Pavel B Kopnin, Nadezhda V Elkina, Alexey N Katargin, Radik S Faskhutdinov, Diana I Salnikova, Alexander M Scherbakov, Mikhail A Krasil'nikov.

Aim: Resistance to hormonal and targeted therapies in breast cancer limits treatment efficacy. Epigenetic alterations, including changes mediated by DNA methyltransferases, play a key role in this process. Previously, we identified that resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A. This study aims to further explore the mechanisms underlying this suppression, with a focus on identifying NR6A1 as a novel regulatory factor. Methods: Acquisition of resistant breast cancer cell sublines, MTT-test, immunoblotting, transient transfection and reporter analysis, lentiviral infection, qRT-PCR, and analysis of methylation using bisulfite pyrosequencing. Results: Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation. Conclusion: The coordinated suppression of NR6A1 and DNMT3A may contribute to sustaining the resistant phenotype in breast cancer cells. This pathway could serve as a predictive marker, helping guide the selection of optimal therapeutic strategies for breast cancer treatment in the future.

Keywords: Breast cancer; DNMT3A; MCF-7 cells; NR6A1; Snail; estrogen receptor α; methylation; rapamycin; tamoxifen

DOI: https://doi.org/10.20517/cdr.2024.69