Triple-negative breast cancer molecular subtyping and treatment progress

Yin, Li; Jiang, Duan; Bian, Xiu Wu; Yu, Shi Cang

doi:10.1186/s13058-020-01296-5

Cited by 1,343 publications

(1,220 citation statements)

References 88 publications

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“…TNBC is the most aggressive form of the disease with high frequency of recurrence and high risk for distant metastases, mostly to the brain and the lungs. Unfortunately, there is no specific targeted therapy for TNBC patients 1,2 …”

Section: Introductionmentioning

confidence: 99%

Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

Alraouji

Aboussekhra

2020

Molecular Carcinogenesis

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Triple‐negative breast cancer (TNBC) is the most aggressive subtype of the disease with lack of recognized molecular targets for therapy. TNBC cells are known to secrete high levels of the proinflammatory cytokines interleukin‐6 (IL‐6) and IL‐8, which promote angiogenesis and favor the growth and spread of the disease. In the present study, we have shown that the humanized anti‐IL‐6 receptor tocilizumab (Actemra) is also a potent inhibitor of IL‐8 in TNBC cells. Similar effect was also obtained by specific IL‐6 inhibition either by small interfering RNA or by neutralizing antibody. Likewise, neutralizing IL‐8 with specific antibody downregulated IL‐8 and inhibited the IL‐6/signal transducer and activator of transcription 3 and nuclear factor‐κB pathways. Interestingly, simultaneous co‐inhibition of IL‐6 and IL‐8 did not increase the effects of the single inhibitors. Additionally, we present clear evidence that tocilizumab has potent antiangiogenic effect. Indeed, tocilizumab abolished the ability of TNBC cells to induce the differentiation of endothelial cells into network‐like tubular structures in vitro and impaired neovascularization in humanized breast orthotopic tumor xenografts. This was associated with tocilizumab‐dependent downregulation of the main proangiogenic factor vascular endothelial growth factor A and its coactivator hypoxia‐inducible factor 1 both in vitro and in vivo. Therefore, tocilizumab could be of great therapeutic value for TNBC patients through targeting angiogenesis.

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Section: Introductionmentioning

confidence: 99%

Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

Alraouji

Aboussekhra

2020

Molecular Carcinogenesis

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“…We specifically picked these two subtypes of breast cancer based on their tropism for bone metastases. Triple negative breast cancer is considered a highly aggressive subtype of breast cancer, because it grows quickly, rapidly spreads to other organs, including bone, and is associated with high chemotherapy resistance [ 93 , 94 ]. Conversely, ER+ breast cancer has been shown to remain in a growth suppressive state in the skeleton for up to three decades in individuals with this breast cancer subtype [ 95 , 96 ].…”

Section: Discussionmentioning

confidence: 99%

‘Educated’ Osteoblasts Reduce Osteoclastogenesis in a Bone-Tumor Mimetic Microenvironment

Kolb

Dai

Keller

et al. 2021

Cancers

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Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on a bone mimetic matrix to assess osteoclast resorption. Pre-osteoclasts were tri-cultured with EOs plus metastatic BC cells and assessed for tartrate-resistance acid phosphatase (TRAP)-positive, multinucleated (≥3 nuclei), mature osteoclasts. Tumor-bearing murine tibias were stained for TRAP to determine osteoclast number in-vivo. EO CM expressed reduced amounts of soluble TNFα and OPG compared to naïve osteoblast CM. Osteoclasts formed in the presence of EOs were smaller and less in number. Upon co-culture on a mimetic bone matrix, a 50% reduction in the number of TRAP-positive osteoclasts formed in the presence of EOs was observed. The tibia of mice inoculated with BC cells had less osteoclasts per bone surface in bones with increased numbers of EO cells. These data suggest EOs reduce osteoclastogenesis and bone resorption. The data imply EOs provide a protective effect against bone resorption in bone metastatic BC.

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“…Of the BCs, TNBC is considered to be the most aggressive. Due to limited treatment options, conventional chemotherapeutic agents such as taxanes or anthracyclines are often used to treat TNBC patients in the clinic; however, these chemotherapeutic agents exhibit relatively low selectivity, thus causing severe side-effects [ 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of DOT1L by Half-Selenopsammaplin A Analogs Suppresses Tumor Growth and EMT-Mediated Metastasis in Triple-Negative Breast Cancer

et al. 2020

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Due to a lack of hormone receptors, current treatment strategies for triple-negative breast cancer (TNBC) are limited with frequent disease recurrence and metastasis. Recent findings have suggested that aberrant methylation of histone H3 lysine 79 residue (H3K79me) by the histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is a potential therapeutic target for TNBC clinical management. Therefore, we developed DOT1L inhibitors as potential antitumor agents against TNBC cells. We reveal that a synthetic half-selenopsammaplin A analog 9l (subsequently known as 9l) exhibited inhibitory activity against DOT1L-mediated H3K79 methylation, and showed antitumor activity in TNBC cells. The analog 9l also significantly inhibited TNBC invasion and migration via the modulation of epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin downregulation and E-cadherin upregulation. In an MDA-MB-231/Luc-implanted orthotopic mouse metastasis model, treatment with 9l effectively inhibited tumor growth and lung metastasis via DOT1L regulatory activity and EMT processes. Taken together, these findings highlight the potential of 9l as a novel therapeutic candidate for treating metastatic TNBC via DOT1L modulation.

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Triple-negative breast cancer molecular subtyping and treatment progress

Cited by 1,343 publications

References 88 publications

Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

Tocilizumab inhibits IL‐8 and the proangiogenic potential of triple negative breast cancer cells

‘Educated’ Osteoblasts Reduce Osteoclastogenesis in a Bone-Tumor Mimetic Microenvironment

Inhibition of DOT1L by Half-Selenopsammaplin A Analogs Suppresses Tumor Growth and EMT-Mediated Metastasis in Triple-Negative Breast Cancer

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