Breast Cancer Metastasis: Mechanisms and Therapeutic Implications

Park, Misung; Kim, Do-Hee; Ko, Sunghyub; Kim, Ayoung; Mo, Kyumin; Yoon, Hyunho

doi:10.3390/ijms23126806

Cited by 135 publications

(98 citation statements)

References 123 publications

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“…EMT is one of the critical mechanisms in breast cancer metastasis [ 5 , 40 ]. Abnormal regulation of EGFR signaling in tumors usually leads to changes in cell proliferation and adhesion, increasing cell aggressiveness and motility, which are hallmarks of EMT and the initial stages of tumorigenesis [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Metastasis as a representative hallmark of most cancers is primarily responsible for the death from breast cancer [ 3 , 4 ]. It is a cellular process through several mechanisms including epithelial-mesenchymal transition (EMT), by which breast cancer cells cross the surrounding basement membrane and enter the vascular system to spread into distant organs, leading to resistance to therapy and treatment failure [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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PELI1 and EGFR cooperate to promote breast cancer metastasis

et al. 2023

Oncogenesis

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Pellino-1 (PELI1) is an E3 ubiquitin ligase acting as a key regulator for the inflammation and autoimmunity via the ubiquitination of the substrate proteins. There is increasing evidence to support that PELI1 functions as an oncoprotein in tumorigenesis and metastasis. However, the molecular mechanism underlying the high expression and oncogenic roles of PELI1 in cancers remains limited. Herein, we revealed a novel regulation mechanism by which PELI1 and EGFR cooperate to promote breast cancer metastasis. EGFR is positively correlated with PELI1 expression in breast cancers, and its activation led to the phosphorylation of PELI1 at Tyr154 and Thr264, which subsequently activated its E3 ubiquitin ligase. Simultaneously, PELI1 physically interacted with and enhanced the stability of EGFR via the K63-linked polyubiquitination in reverse. The co-inhibition of the PELI1-EGFR showed synergetic effect to repress breast cancer metastasis. Furthermore, we identified a compound S62 as a small molecule disruptor of PELI1/EGFR that effectively repressed breast cancer metastasis. Our study not only uncovered the emerging roles of PELI1/EGFR interaction in the progression of breast cancer, but also provided an effective strategy for the inhibition of metastasis in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PELI1 and EGFR cooperate to promote breast cancer metastasis

et al. 2023

Oncogenesis

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“…Breast cancer metastasis is a highly complicated and multifactorial process, including division from the primary tumor, degradation of the basement membrane from the lumen, invasion into the fibrous stroma surrounding the tumor cells, migration through blood and lymph vessels, and the secondary tumor lesion at a distal tissue. 22,23 Accumulating evidence has shown that invasive breast cancer is frequently associated with the spread of the activated stroma. 24 Myofibroblasts, which are a pivotal component of the tumor microenvironment, directly interact with tumor cells to facilitate the malignant progression of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

ZNF32 prevents the activation of cancer‐associated fibroblasts through negative regulation of TGFB1 transcription in breast cancer

Yuan

Zhao

et al. 2023

The FASEB Journal

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Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer‐related deaths in women worldwide. Cancer‐associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF‐related markers (FSP1, α‐SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency‐mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the −1968/−1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF‐β stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.

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“…At present, the annual incidence rate of breast cancer in China has reached 3-4%, and the onset age is reducing, which seriously affects the health and quality of life of female patients (3). Tumor metastasis is an important factor affecting the surgical prognosis of patients with breast cancer, and certain studies have confirmed that 90% of patient mortalities can be attributed to breast cancer metastasis (4,5). Therefore, it is of great importance to further study the mechanisms of breast cancer metastasis and to identify effective targets to inhibit breast cancer metastasis.…”

Section: Introductionmentioning

confidence: 99%

A20 affects macrophage polarization through the NLRP3 inflammasome signaling pathway and promotes breast cancer progression

et al. 2023

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Breast cancer is the most common malignant tumor in females, and the majority of patients succumb to metastasis. The present study aimed to investigate the association between tumor necrosis factor alpha-induced protein 3 (A20), NOD-, LRR-and pyrin domain-containing protein 3 (NLRP3) and tumor-associated macrophage polarization, and their effects on the proliferation and metastasis of breast cancer cells. The expression of A20 in breast cancer cells was analyzed by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. RT-qPCR and western blotting were also used to confirm the transfection efficiency. The viability, clone formation, migration, invasion and angiogenesis of transfected breast cancer cells were detected by Cell Counting Kit-8, colony formation, wound healing, Transwell and tube formation assays, respectively. Activated macrophages, namely M1 and M2 type macrophages, were observed by double staining immunofluorescence. The levels of M1 and M2 macrophage markers were analyzed by qPCR. The expression of angiogenesis-related proteins and NLRP3 inflammasome activation-associated proteins was detected by western blotting. The results revealed that A20 was highly expressed in breast cancer cells. Interference with A20 inhibited the proliferation, invasion, migration and angiogenesis of breast cancer cells, and inhibited the M2-like polarization of macrophages. Interference with A20 promoted the activation of the NLRP3 inflammasome. The NLRP3 inhibitor MCC950 alleviated the effect of interference with A20 to promote macrophage proliferation and recruitment, as well as M2-like polarization. In conclusion, interference with A20 inhibited macrophage proliferation and M2-like polarization through the NLRP3 inflammasome signaling pathway to inhibit breast cancer progression.

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Breast Cancer Metastasis: Mechanisms and Therapeutic Implications

Cited by 135 publications

References 123 publications

PELI1 and EGFR cooperate to promote breast cancer metastasis

PELI1 and EGFR cooperate to promote breast cancer metastasis

ZNF32 prevents the activation of cancer‐associated fibroblasts through negative regulation of TGFB1 transcription in breast cancer

A20 affects macrophage polarization through the NLRP3 inflammasome signaling pathway and promotes breast cancer progression

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