Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN) Derived from Bone Marrow Stromal Cells Promotes the Development of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) remains a threat to women’s life with a lack of targeted therapy. This study aimed to explore the role of PTEN derived from BMSCs in TNBC. We carried out a retrospective analysis of 65 TNBC patients and 30 healthy subjects from October 2016 to January 2021 with a 10-year follow up. PTEN expression in TNBC tissues and cells was determined by RTqPCR. Functional experiments were conducted to evaluate PTEN’s effect on TNBC cell biological behaviors using MTT assay and Transwell assay, as well as on PI3K-Akt-HIF-1α-VEGF signaling transduction. PTEN was up-regulated in TNBC tissues relative to healthy controls and it was negatively associated with the survival rate. In in vitro experiments, PTEN overexpression increased cell viability and invasion and knocking down of PTEN exerted opposite effect. The expression of PI3K was directly regulated by PTEN. Up-regulation of PTEN resulted in a decline in HIF-1α, Akt and VEGF expressions, which were elevated after knocking down of PTEN. In conclusion, PTEN derived from BMSCs promotes TNBC cell development through blocking PI3K-Akt-HIF-1α-VEGF signaling pathway, providing a new theoretical basis for targeted therapy of TNBC.

Prospects of Immunotherapy for Triple-Negative Breast Cancer

In the classification and typing of breast cancer, triple-negative breast cancer (TNBC) is one type of refractory breast cancer, while chemotherapy stays in the traditional treatment methods. However, the impact of chemotherapy is short-lived and may lead to recurrence due to incomplete killing of tumor cells. The occurrence, development, and relapse of breast cancer are relevant to T cell dysfunction, multiplied expression of related immune checkpoint molecules (ICIs) such as programmed death receptor 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) produce immunosuppressive effect. Immunotherapy (namely, immune checkpoint inhibitors, adoptive cellular immunotherapy, CAR-T immunotherapy and some potential treatments) provides new hope in TNBC. This review focuses on the new immune strategies of TNBC patients.

Survival, treatment regimens and medical costs of women newly diagnosed with metastatic triple-negative breast cancer

Individuals diagnosed with metastatic triple-negative breast cancer (mTNBC) suffer worse survival rates than their metastatic non-TNBC counterparts. There is little information on survival, treatment patterns, and medical costs of mTNBC patients in Asia. Therefore, this study aimed to examine 5-year survival, regimens of first-line systemic therapy, and healthcare costs of mTNBC patients in Taiwan. Adult females newly diagnosed with TNBC and non-TNBC as well as their survival data, treatment regimens and costs of health services were identified and retrieved from the Cancer Registry database, Death Registry database, and National Health Insurance (NHI) claims database. A total of 9691 (19.27%) women were identified as TNBC among overall BC. The 5-year overall survival rate of TNBC and non-TNBC was 81.28% and 86.50%, respectively, and that of mTNBC and metastatic non-TNBC was 10.81% and 33.46%, respectively. The majority of mTNBC patients received combination therapy as their first-line treatment (78.14%). The 5-year total cost in patients with metastatic non-TNBC and with mTNBC was NTD1,808,693 and NTD803,445, respectively. Higher CCI scores were associated with an increased risk of death and lower probability of receiving combination chemotherapy. Older age was associated with lower 5-year medical costs. In sum, mTNBC patients suffered from poorer survival and incurred lower medical costs than their metastatic non-TNBC counterparts. Future research will be needed when there are more treatment options available for mTNBC patients.

Systemic HER3 ligand-mimicking bioparticles cross the blood–brain barrier reducing intracranial triple-negative breast cancer growth

Triple-negative breast cancer (TNBC) lacks selective biomarkers targeted by current clinical therapies and often metastasizes to the brain. Crossing the blood-brain barrier (BBB) and reaching intracranial tumors is a clinical challenge contributing to poor prognoses for patients. The human epidermal growth factor receptor HER3 has emerged as a biomarker of metastasis and may provide a means of therapeutically targeting TNBC. We have developed HER3-targeted biological particles (bioparticles) that exhibit systemic homing to resistant and metastatic breast tumors. Here we show that HER3 is expressed on the brain endothelium and can mediate the passage of bioparticles across the BBB and into intracranial TNBC. Our findings show that the extravasation of systemic bioparticles in mice and in human induced pluripotent stem cell-based BBB chips corresponds to HER3 levels. Furthermore, systemically delivered bioparticles carrying tumoricidal agents reduced the growth of intracranial TNBC in mice and exhibited improved therapeutic profile compared to current therapies.

Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.

Mitotic kinesin-like protein 1, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway

Background: Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. MKLP1 plays a crucial role in tumorigenesis and cancer progression. However, the role of MKLP1 in triple negative breast cancer and the underlying mechanism remain unknown. The study aimed to elucidate the biological function regulatory mechanism of MKLP1 in triple negative breast cancerMethods: Quantitative real-time PCR and Western blotting were used to determine the MKLP1 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of MKLP1 on tumor growth and metastasis in triple negative breast cancer. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of MKLP1 in triple negative breast cancer.Results: We found that MKLP1 was significantly up-regulated and associated with poor prognosis in triple negative breast cancer. MKLP1 could promote triple negative breast cancer proliferation, migration and invasion in vitro and in vivo. MKLP1 could activate Wnt/β-catenin pathway and promote EMT progression. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of MKLP1 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions: Our findings elucidate WDR5/FOXM1/MKLP1/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.