Metastatic Breast Cancer, Organotropism and Therapeutics: A Review

Waza, Ajaz Ahmad; Tarfeen, Najeebul; Majid, Sabhiya; Hassan, Yasmeena; Mir, Rashid; Rather, Mohd Younis; Shah, Naseer Ue Din

doi:10.2174/1568009621666210806094410

Cited by 7 publications

(3 citation statements)

References 197 publications

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“…1 One of the gravest consequences of breast cancer is its propensity to metastasize to vital organs such as the liver, brain, lungs and bones during the middle and late stages, leading to the deterioration of these target organs, impairment of their function and ultimately resulting in the demise of patients. 2 Bone metastases are particularly prevalent in breast cancer, disrupting skeletal homeostasis and initiating a detrimental cycle. 3 A previous report highlighted that brain metastases from breast cancer are frequently observed in cases of human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancers.…”

Section: Introductionmentioning

confidence: 99%

Construction of an oxidative stress-associated genes signature in breast cancer by machine learning algorithms

Hu,

Qin,

Zhang

et al. 2024

J Int Med Res

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Objective To construct a prognostic model of a breast cancer-related oxidative stress-related gene (OSRG) signature using machine learning algorithms. Methods The OSRGs of breast cancer were constructed by least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. The Cancer Genome Atlas (TCGA) was used to analyse the gene expression and prognostic value. The Human Protein Atlas was used to analyse the protein expression of hub genes. Receiver operating characteristic analysis, calibration curve and decision curve analysis were used to predict the stability of this model. Results The area under the curve of 1-, 3- and 5-year overall survival were 0.751, 0.707 and 0.645 in the TCGA training dataset; and 0.692, 0.678 and 0.602 in the TCGA testing dataset, respectively. Calibration plot showed good agreement between predicted probabilities and observed outcomes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) pathway analysis indicated that multiple cancer-related pathways were highly enriched in the high-risk group. Immune infiltration analysis showed immune cells and their functions may play a key role in the development and mechanism of breast cancer. Conclusions This new OSRG signature was associated with the immune infiltration and it might be useful in predicting the prognosis in patients with breast cancer.

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Section: Introductionmentioning

confidence: 99%

Construction of an oxidative stress-associated genes signature in breast cancer by machine learning algorithms

Hu,

Qin,

Zhang

et al. 2024

J Int Med Res

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“…Despite advancements made in the diagnosis and treatment of breast cancer, there is still a risk of recurrence and distant metastasis, which is the main cause of breast cancer-related deaths [ 2 ]. Currently, the mechanism of BRCA metastasis is not yet fully understood, and it remains a challenge in the prevention and treatment of metastatic BRCA [ 3 ]. Therefore, in-depth research on the molecular mechanisms involved in BRCA development and progression is crucial for finding the biomarkers for the early prediction of metastatic risk, identifying therapeutic targets, and improving therapeutic strategies, all of which can reduce BRCA mortality and benefit patients.…”

Section: Introductionmentioning

confidence: 99%

FRMD3 inhibits the growth and metastasis of breast cancer through the ubiquitination-mediated degradation of vimentin and subsequent impairment of focal adhesion

Shao

Piao

et al. 2023

Cell Death Dis

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Recurrence and metastasis are the main causes of breast cancer (BRCA)-related death and remain a challenge for treatment. In-depth research on the molecular mechanisms underlying BRCA progression has been an important basis for developing precise biomarkers and therapy targets for early prediction and treatment of progressed BRCA. Herein, we identified FERM domain-containing protein 3 (FRMD3) as a novel potent BRCA tumor suppressor which is significantly downregulated in BRCA clinical tissue and cell lines, and low FRMD3 expression has been closely associated with progressive BRCA and shortened survival time in BRCA patients. Overexpression and knockdown experiments have revealed that FRMD3 significantly inhibits BRCA cell proliferation, migration, and invasion in vitro and suppresses BRCA xenograft growth and metastasis in vivo as well. Mechanistically, FRMD3 can interact with vimentin and ubiquitin protein ligase E3A(UBE3A) to induce the polyubiquitin-mediated proteasomal degradation of vimentin, which subsequently downregulates focal adhesion complex proteins and pro-cancerous signaling activation, thereby resulting in cytoskeletal rearrangement and defects in cell morphology and focal adhesion. Further evidence has confirmed that FRMD3-mediated vimentin degradation accounts for the anti-proliferation and anti-metastasis effects of FRMD3 on BRCA. Moreover, the N-terminal ubiquitin-like domain of FRMD3 has been identified as responsible for FRMD3-vimentin interaction through binding the head domain of vimentin and the truncated FRMD3 with the deletion of ubiquitin-like domain almost completely loses the anti-BRCA effects. Taken together, our study indicates significant potential for the use of FRMD3 as a novel prognosis biomarker and a therapeutic target of BRCA and provides an additional mechanism underlying the degradation of vimentin and BRCA progression.

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“…From these and other studies, organ colonization emerged as a main rate-limiting step in the metastatic cascade, including in the brain ( 26 , 27 ). Targeting organ colonization, rather than tumor cell dissemination and homing to distant organs, is a highly attractive therapeutic approach, as in patients metastatic cells have already disseminated before primary tumor diagnosis ( 16 , 18 , 28 ).…”

Section: Introductionmentioning

confidence: 99%

Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation

et al. 2022

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Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases. Here, we describe a unique and robust spontaneous preclinical model of breast cancer metastasis to the brain (4T1-BM 2 ) in mice that has been instrumental in uncovering molecular mechanisms guiding metastatic dissemination and colonization of the brain. Key experimental findings were validated in the additional murine D2A1-BM 2 model and in human MDA231-BrM 2 model. Gene expression analyses and functional studies, coupled with clinical transcriptomic and histopathological investigations, identified connexins (Cxs) and focal adhesion kinase (FAK) as master molecules orchestrating breast cancer colonization of the brain. Cx31 promoted homotypic tumor cell adhesion, heterotypic tumor-astrocyte interaction, and FAK phosphorylation. FAK signaling prompted NF-κB activation inducing Lamc2 expression and laminin 332 (laminin 5) deposition, α6 integrin–mediated adhesion, and sustained survival and growth within brain parenchyma. In the MDA231-BrM 2 model, the human homologous molecules CX43, LAMA4, and α3 integrin were involved. Systemic treatment with FAK inhibitors reduced brain metastasis progression. In conclusion, we report a spontaneous model of breast cancer metastasis to the brain and identified Cx-mediated FAK–NF-κB signaling as a mechanism promoting cell-autonomous and microenvironmentally controlled cell survival for brain colonization. Considering the limited therapeutic options for brain metastatic disease in cancer patients, we propose FAK as a therapeutic candidate to further pursue in the clinic.

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Metastatic Breast Cancer, Organotropism and Therapeutics: A Review

Cited by 7 publications

References 197 publications

Construction of an oxidative stress-associated genes signature in breast cancer by machine learning algorithms

Construction of an oxidative stress-associated genes signature in breast cancer by machine learning algorithms

FRMD3 inhibits the growth and metastasis of breast cancer through the ubiquitination-mediated degradation of vimentin and subsequent impairment of focal adhesion

Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation

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