Browsing by Author "Takabe, Kazuaki"

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    Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer
    (Sage, 2021-04-05) Katsuta, Eriko; Yan, Li; Opyrchal, Mateusz; Kalinski, Pawel; Takabe, Kazuaki; Medicine, School of Medicine
    Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC.
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    Increased PIEZO1 Expression Is Associated with Worse Clinical Outcomes in Hormone-Receptor-Negative Breast Cancer Patients
    (MDPI, 2024-02-06) Poole, Rylee Ann; Wang, Qingfei; Ray, Alo; Takabe, Kazuaki; Opyrchal, Mateusz; Katsuta, Eriko; Medicine, School of Medicine
    PIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. An analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis. We also analyzed the immune cell composition in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that the PIEZO1 expression levels are higher in hormone-receptor (HR)-negative than in HR-positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR-negative cohorts, especially in triple-negative breast cancer (TNBC), suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR-negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high-PIEZO1 HR-negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high-PIEZO1 HR-negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR-negative breast cancer.
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    Mechano-Sensing Channel PIEZO2 Enhances Invasive Phenotype in Triple-Negative Breast Cancer
    (MDPI, 2022-08-31) Katsuta, Eriko; Takabe, Kazuaki; Vujcic, Marija; Gottlieb, Philip A.; Dai, Tao; Mercado-Perez, Arnaldo; Beyder, Arthur; Wang, Qingfei; Opyrchal, Mateusz; Medicine, School of Medicine
    Background: Mechanically gated PIEZO channels lead to an influx of cations, activation of additional Ca2+ channels, and cell depolarization. This study aimed to investigate PIEZO2’s role in breast cancer. Methods: The clinical relevance of PIEZO2 expression in breast cancer patient was analyzed in a publicly available dataset. Utilizing PIEZO2 overexpressed breast cancer cells, and in vitro and in vivo experiments were conducted. Results: High expression of PIEZO2 was correlated with a worse survival in triple-negative breast cancer (TNBC) but not in other subtypes. Increased PEIZO2 channel function was confirmed in PIEZO2 overexpressed cells after mechanical stimulation. PIEZO2 overexpressed cells showed increased motility and invasive phenotypes as well as higher expression of SNAIL and Vimentin and lower expression of E-cadherin in TNBC cells. Correspondingly, high expression of PIEZO2 was correlated with the increased expression of epithelial–mesenchymal transition (EMT)-related genes in a TNBC patient. Activated Akt signaling was observed in PIEZO2 overexpressed TNBC cells. PIEZO2 overexpressed MDA-MB-231 cells formed a significantly higher number of lung metastases after orthotopic implantation. Conclusion: PIEZO2 activation led to enhanced SNAIL stabilization through Akt activation. It enhanced Vimentin and repressed E-cadherin transcription, resulting in increased metastatic potential and poor clinical outcomes in TNBC patients.
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    Systemic Therapy De-Escalation in Early-Stage Triple-Negative Breast Cancer: Dawn of a New Era?
    (MDPI, 2022-04-07) Gupta, Ravi Kumar; Roy, Arya Mariam; Gupta, Ashish; Takabe, Kazuaki; Dhakal, Ajay; Opyrchal, Mateusz; Kalinski, Pawel; Gandhi, Shipra; Medicine, School of Medicine
    Early-stage triple negative breast cancer (TNBC) has been traditionally treated with surgery, radiation, and chemotherapy. The current standard of care systemic treatment of early-stage II and III TNBC involves the use of anthracycline-cyclophosphamide and carboplatin-paclitaxel with pembrolizumab in the neoadjuvant setting followed by adjuvant pembrolizumab per KEYNOTE-522. It is increasingly clear that not all patients with early-stage TNBC need this intensive treatment, thus paving the way for exploring opportunities for regimen de-escalation in selected subgroups. For T1a tumors (≤5 mm), chemotherapy is not used, and for tumors 6-10 mm (T1b) in size with negative lymph nodes, retrospective studies have failed to show a significant benefit with chemotherapy. In low-risk patients, anthracycline-free chemotherapy may be as effective as conventional therapy, as shown in some studies where replacing anthracyclines with carboplatin has shown non-inferior results for pathological complete response (pCR), which may form the backbone of future combination therapies. Recent advances in our understanding of TNBC heterogeneity, mutations, and surrogate markers of response such as pCR have enabled the development of multiple treatment options in the (neo)adjuvant setting in order to de-escalate treatment. These de-escalation studies based on tumor mutational status, such as using Poly ADP-ribose polymerase inhibitors (PARPi) in patients with BRCA mutations, and new immunotherapies such as PD1 blockade, have shown a promising impact on pCR. In addition, the investigational use of (bio)markers, such as high levels of tumor-infiltrating lymphocytes (TILs), low levels of tumor-associated macrophages (TAMs), and complete remission on imaging, also look promising. In this review, we cover the current standard of care systemic treatment of early TNBC and review the opportunities for treatment de-escalation based on clinical risk factors, biomarkers, mutational status, and molecular subtype.
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    Targeting PIM2 by JP11646 results in significant antitumor effects in solid tumors
    (Spandidos, 2022) Katsuta, Eriko; Gil-Moore, Malgorzata; Moore, Justine; Yousif, Mohamed; Adjei, Alex A.; Ding, Yi; Caserta, Justin; Baldino, Carmen M.; Lee, Kelvin P.; Gelman, Irwin H.; Takabe, Kazuaki; Opyrchal, Mateusz; Medicine, School of Medicine
    Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The pan‑PIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentration‑dependent manner in multiple types of cancers; a similar result was observed with siRNA‑mediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another pan‑PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome‑dependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.