Role of PTEN, PI3K, and mTOR in Triple-Negative Breast Cancer

Breast cancer is the most commonly occurring malignancy and the leading cause of cancer-related death in women. Triple-negative breast cancer (TNBC) is the most aggressive subtype and is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival. The aim of this study was to investigate the PI3K/PTEN/Akt/mTOR pathway as one of the most frequently deregulated pathways in cancer. We aimed to explore the impact of PI3K and mTOR oncogenes as well as the PTEN tumor suppressor on TNBC clinical behavior, prognosis, and multidrug resistance (MDR), using immunohistochemistry and copy number analysis by quantitative real-time PCR. Our results revealed that loss of PTEN and high expression of PI3K and mTOR proteins are associated with poor outcome of TNBC patients. PTEN deletions appeared as a major cause of reduced or absent PTEN expression in TNBC. Importantly, homozygous deletions of PTEN (and not hemizygous deletions) are a potential molecular marker of metastasis formation and good predictors of TNBC outcome. In conclusion, we believe that concurrent examination of PTEN/PI3K/mTOR protein expression may be more useful in predicting TNBC clinical course than the analysis of single protein expression. Specifically, our results showed that PTEN-reduced/PI3K-high/mTOR-high expression constitutes a ‘high risk’ profile of TNBC.

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VDAC1 Conversely Correlates with Cytc Expression and Predicts Poor Prognosis in Human Breast Cancer Patients

10.21203/rs.3.rs-31811/v1 ◽

2020 ◽

Author(s):

Fangfang Chen ◽

Shuai Yin ◽

Bin Luo ◽

Xiaoyan Wu ◽

Honglin Yan ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factor ◽

Protein Expression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Histological Grade ◽

High Expression ◽

Voltage Dependent Anion Channel ◽

Poor Prognostic Factor ◽

Independent Poor Prognostic Factor

Abstract AIM: The main objectives of this article were to evaluate the association of voltage-dependent anion channel 1 (VDAC1) expression with Cytochrome C (Cytc) protein, various clinicopathological features and prognosis in patients diagnosed with breast cancer (BC). Meanwhile, the correlation of Cytc expression with various clinical features and 5-year disease-free survival (5-DFS) of BC is also investigated. Methods: Expression of VDAC1 protein and Cytc protein was conducted in 219 BC patients and 60 benign breast lesions by immunohistochemical (IHC) analysis. Results: In our study, VDAC1 protein expression was significantly increased while Cytc protein was decreased in breast tumor tissues (P = 0.015 and P = 0.029, respectively). High expression of VDAC1 is conversely associated with Cytc expression in BC, especially in triple-negative breast cancer (TNBC) (P = 0.011 and P = 0.004, respectively). Interestingly, high expression of VDCA1 not only had a significant association with advanced TNM stage, histological grade, LNM, HER2 gene amplification and recurrence (P < 0.05), but also displayed a poorer 5-DFS (P < 0.001) in BC. The multivariate Cox proportional hazard model demonstrated VDAC1 as a novel independent poor prognostic factor in BC (P = 0.001). Strikingly, our study also showed the prognostic significance of VDAC1 in triple-negative breast cancer in particular. Furthermore, low expression of Cytc was found to be correlated with histological grade, ER status, PR status and recurrence in BC (P < 0.05). Kaplan-Meier analysis indicated that low Cytc expression was associated with poorer survival and high mortality rate (P = 0.007). Cytc protein expression also served as a novel independent prognosis parameters in BC patients (P = 0.035). Conclusion: Our findings firstly revealed that VDAC1 was elevated in BC tissues and conversely associated with Cytc. Furthermore, high VDAC1 protein was associated with reduced 5-DFS and could be acted as an independent poor prognostic factor not only in breast cancer in general, but also in TNBC in particular. All in all, VDAC1 can be exploited as a potential prognostic marker and therapeutic target in BC, especially in TNBC.

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Metabotropic glutamate receptor 1 is associated with unfavorable prognosis in ER-negative and triple-negative breast cancer

Scientific Reports ◽

10.1038/s41598-020-79248-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Anna E. M. Bastiaansen ◽

A. Mieke Timmermans ◽

Marcel Smid ◽

Carolien H. M. van Deurzen ◽

Esther S. P. Hulsenboom ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Glutamate Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Metabotropic Glutamate Receptor ◽

Metabotropic Glutamate ◽

Metabotropic Glutamate Receptor 1 ◽

Novel Target ◽

Cancer Tissues

AbstractNew therapies are an urgent medical need in all breast cancer subgroups. Metabotropic glutamate receptor 1 (mGluR1) is suggested as a potential new molecular target. We examined the prevalence mGluR1 expression in different clinically relevant breast cancer subgroups and determined its association with prognosis. In this retrospective cohort, 394 consecutive primary breast cancer tissues were incorporated into a tissue microarray and immunohistochemically stained for mGluR1. The prevalence of mGluR1 protein expression in different breast cancer subgroups was evaluated and correlated with metastasis-free survival (MFS) and overall survival (OS). In total, 56% (n = 219) breast cancer tissues had mGluR1 expression. In estrogen receptor (ER)-negative tumors, 31% (n = 18/58) had mGluR1 expression that was significantly associated with MFS (HR 5.00, 95% CI 1.03–24.35, p = 0.046) in multivariate analysis, independently from other prognostic factors. Of the 44 triple-negative breast cancer (TNBC), 25% (n = 11) expressed mGluR1. mGluR1 expression in TNBC was significantly associated with shorter MFS (HR 8.60, 95% CI 1.06–20.39, p = 0.044) and with poor OS (HR 16.07, 95% CI 1.16–223.10, p = 0.039). In conclusion, mGluR1 is frequently expressed in breast cancer. In ER-negative breast cancer and in TNBC mGluR1 protein expression is an unfavorable prognostic marker. This study provides rationale to explore mGluR1 as a novel target for breast cancer treatment, especially for the more aggressive TNBC.

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PITX2 DNA-Methylation: Predictive versus Prognostic Value for Anthracycline-Based Chemotherapy in Triple-Negative Breast Cancer Patients

Breast Care ◽

10.1159/000510468 ◽

2020 ◽

pp. 1-9

Author(s):

Rudolf Napieralski ◽

Gabriele Schricker ◽

Gert Auer ◽

Michaela Aubele ◽

Jonathan Perkins ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Cancer Patients ◽

Triple Negative Breast Cancer ◽

Predictive Value ◽

Untreated Patient ◽

Triple Negative ◽

Statistical Significance ◽

Breast Cancer Patients ◽

The Impact

Background: PITX2 DNA methylation has been shown to predict outcomes in high-risk breast cancer patients after anthracycline-based chemotherapy. To determine its prognostic versus predictive value, the impact of PITX2 DNA methylation on outcomes was studied in an untreated cohort vs. an anthracycline-treated triple-negative breast cancer (TNBC) cohort. Material and Methods: The percent DNA methylation ratio (PMR) of paired-like homeodomain transcription factor 2 (PITX2) was determined by a validated methylation-specific real-time PCR test. Patient samples of routinely collected archived formalin-fixed paraffin-embedded (FFPE) tissue and clinical data from 144 TNBC patients of 2 independent cohorts (i.e., 66 untreated patients and 78 patients treated with anthracycline-based chemotherapy) were analyzed. Results: The risk of 5- and 10-year overall survival (OS) increased continuously with rising PITX2 DNA methylation in the anthracycline-treated population, but it increased only slightly during 10-year follow-up time in the untreated patient population. PITX2 DNA methylation with a PMR cutoff of 2 did not show significance for poor vs. good outcomes (OS) in the untreated patient cohort (HR = 1.55; p = 0.259). In contrast, the PITX2 PMR cutoff of 2 identified patients with poor (PMR >2) vs. good (PMR ≤2) outcomes (OS) with statistical significance in the anthracycline-treated cohort (HR = 3.96; p = 0.011). The results in the subgroup of patients who did receive anthracyclines only (no taxanes) confirmed this finding (HR = 5.71; p = 0.014). Conclusion: In this hypothesis-generating study PITX2 DNA methylation demonstrated predominantly predictive value in anthracycline treatment in TNBC patients. The risk of poor outcome (OS) correlates with increasing PITX2 DNA methylation.

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High expression of UBD correlates with epirubicin resistance and indicates poor prognosis in triple-negative breast cancer

OncoTargets and Therapy ◽

10.2147/ott.s81214 ◽

2015 ◽

pp. 1643 ◽

Cited By ~ 1

Author(s):

Xiaodong Xie ◽

TAO HAN ◽

Yaling Han ◽

Wanqing Xie ◽

Ranran Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Poor Prognosis ◽

Triple Negative ◽

High Expression

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Obesity Modulates the Gut Microbiome in Triple-Negative Breast Cancer

Nutrients ◽

10.3390/nu13103656 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3656

Author(s):

Fokhrul Hossain ◽

Samarpan Majumder ◽

Justin David ◽

Bruce A. Bunnell ◽

Lucio Miele

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Gut Microbiome ◽

Triple Negative ◽

Alpha Diversity ◽

Low Grade ◽

Syngeneic Mouse Model ◽

Variation Of Functional ◽

Analysis Of Variation ◽

The Impact

Triple-negative breast cancer (TNBC) is an aggressive, molecularly heterogeneous subtype of breast cancer. Obesity is associated with increased incidence and worse prognosis in TNBC through various potential mechanisms. Recent evidence suggests that the gut microbiome plays a central role in the progression of cancer, and that imbalances or dysbiosis in the population of commensal microbiota can lead to inflammation and contribute to tumor progression. Obesity is characterized by low-grade inflammation, and gut dysbiosis is associated with obesity, chronic inflammation, and failure of cancer immunotherapy. However, the debate on what constitutes a “healthy” gut microbiome is ongoing, and the connection among the gut microbiome, obesity, and TNBC has not yet been addressed. This study aims to characterize the role of obesity in modulating the gut microbiome in a syngeneic mouse model of TNBC. 16S rRNA sequencing and metagenomic analyses were performed to analyze and annotate genus and taxonomic profiles. Our results suggest that obesity decreases alpha diversity in the gut microbiome. Metagenomic analysis revealed that obesity was the only significant factor explaining the similarity of the bacterial communities according to their taxonomic profiles. In contrast to the analysis of taxonomic profiles, the analysis of variation of functional profiles suggested that obesity status, tumor presence, and the obesity–tumor interaction were significant in explaining the variation of profiles, with obesity having the strongest correlation. The presence of tumor modified the profiles to a greater extent in obese than in lean animals. Further research is warranted to understand the impact of the gut microbiome on TNBC progression and immunotherapy.

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Antiangiogenic therapy for breast cancer with triple negative phenotype

Modern Oncology ◽

10.26442/18151434.2021.1.200763 ◽

2021 ◽

Vol 23 (1) ◽

pp. 88-92

Author(s):

Inna P. Ganshina ◽

Kristina A. Ivanova ◽

Olga O. Gordeeva ◽

Aleksandr V. Arkhipov ◽

Liudmila G. Zhukova

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Malignant Tumors ◽

Antiangiogenic Therapy ◽

Treatment Strategies ◽

Her 2 ◽

Triple Negative Phenotype ◽

The Impact ◽

Negative Phenotype

Triple-negative breast cancer is 1024% of all cases of breast cancer and is characterized by the absence of estrogen, progesterone, and HER-2 receptors in the tumor. The therapy of this illness is a difficult clinical case. In contrast to hormone-positive and HER-2-positive phenotypes, in which we successfully use targeted drugs (antiestrogens and anti-HER-2 drugs), for triple-negative breast cancer we have not had such targets for a long time. Thus, despite the impressive results of immunotherapy of triple-negative breast cancer, there remains a fairly large group of patients with negative PD-L1 status, for whom it is necessary to develop other treatment strategies. One of the approaches in the treatment of malignant tumors includes not the impact on tumor cells, but the process of angiogenesis. Antiangiogenic drugs have positively proven themselves in the treatment of a large number of malignant tumors but are underestimated for breast cancer (including triple-negative phenotype). The use of bevacizumab in combinations with cytostatic drugs in breast cancer therapy (including triple-negative breast cancer) has been studied in a large number of clinical trials but was undeservedly forgotten in some countries due to the revoked FDA registration. This review presents the role of bevacizumab in the treatment of patients with triple-negative breast cancer and suggests the conditions when the administration of this drug is justified and leads to better results.

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