The Biological and Clinical Significance of Glutaminase in Luminal Breast Cancer

The glutamine metabolism has a key role in the regulation of uncontrolled tumour growth. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). The glutaminase isoforms (GLS/GLS2) were assessed at genomic/transcriptomic levels, using METABRIC (n = 1398) and GeneMiner datasets (n = 4712), and protein using immunohistochemistry in well-characterised cohorts of Oestrogen receptor-positive/HER2-negative BC patients: ductal carcinoma in situ (DCIS; n = 206) and invasive breast cancer (IBC; n = 717). Glutaminase expression was associated with clinicopathological features, patient outcome and glutamine-metabolism-related genes. In DCIS, GLS alone and GLS+/GLS2- expression were risk factors for shorter local recurrence-free interval (p < 0.0001 and p = 0.001, respectively) and remained prognostic factors independent of tumour size, grade and comedo necrosis (p = 0.0008 and p = 0.003, respectively). In IBC, GLS gene copy number gain with high mRNA expression was associated with poor patient outcome (p = 0.011), whereas high GLS2 protein was predictive of a longer disease-free survival (p = 0.006). Glutaminase plays a role in the biological function of luminal BC, particularly GLS in the early non-invasive stage, which could be used as a potential biomarker to predict disease progression and a target for inhibition. Further validation is required to confirm these observations, and functional assessments are needed to explore their specific roles.

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The Biological and Clinical Significance of Glutaminase in Luminal Breast Cancer

10.21203/rs.3.rs-93938/v1 ◽

2020 ◽

Author(s):

Brendah Masisi ◽

Rokaya El-Ansari ◽

Lutfi Alfarsi ◽

Madeleine Craze ◽

Natasha Jewa ◽

...

Keyword(s):

Breast Cancer ◽

Patient Outcome ◽

Ductal Carcinoma ◽

Prognostic Significance ◽

Disease Free Survival ◽

Protein Isoforms ◽

Glutamine Metabolism ◽

Gene Copy ◽

Luminal Breast Cancer ◽

Potential Biomarker

Abstract Background: Glutamine metabolism has a key role in the regulation of uncontrolled tumour growth by modulating bioenergetics, redox homeostasis and serving as a precursor for biomass synthesis. Glutaminase is a key enzyme involved in glutaminolysis, a process which plays a crucial role in carcinogenesis and progression. This study aimed to evaluate the expression and prognostic significance of glutaminase in luminal breast cancer (BC). Methods: The glutaminase protein isoforms (GLS and GLS2) were assessed at the genomic and transcriptomic levels, using METABRIC (n=1398) and GENE MINER datasets (n=4,712), and protein level using immunohistochemistry in large well characterised cohorts of luminal Oestrogen Receptor (ER)-positive and HER2-negative BC patients, including ductal carcinoma in situ (DCIS) (n=206) and invasive BC (IBC; n=717) cohorts. GLS and GLS2 expression was associated with clinicopathological features, patient outcome and other glutamine-metabolism related genes. Results: In DCIS, GLS expression was an independent risk factor for shorter local recurrence-free interval (p<0.0008). In IBC high GLS and GLS2 mRNA and protein expression significantly correlated with solute carriers with high glutamine affinity, SLC3A2 (p≤0.01) SLC7A8 (p≤0.01) and SLC7A5 (p<0.001), and glutamine related enzymes; GLUD1 (p<0.001) and ALDH18A1 (p<0.001). GLS and GLS2 gene copy number gains were associated with poor patient outcome (p=0.028; p=0.010 respectively). High GLS2 protein was predictive of a longer disease-free survival (p=0.006). Conclusion: GLS appears to play a role in the early non-invasive stage of BC and it could be used as a potential biomarker to predict DCIS progression to invasive disease. In IBC, both GLS and GLS2 play a key role in the biological function of luminal tumours. Further functional assessments are needed to explore the specific role played by each isoform in BC.

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The prognostic significance of wild-type isocitrate dehydrogenase 2 (IDH2) in breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-019-05459-7 ◽

2019 ◽

Vol 179 (1) ◽

pp. 79-90 ◽

Cited By ~ 3

Author(s):

Abrar I. Aljohani ◽

Michael S. Toss ◽

Sasagu Kurozumi ◽

Chitra Joseph ◽

Mohammed A. Aleskandarany ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Isocitrate Dehydrogenase ◽

Ductal Carcinoma ◽

Tumour Size ◽

Prognostic Significance ◽

Wild Type ◽

Hormonal Receptor ◽

Isocitrate Dehydrogenase 2 ◽

Receptor Negativity

Abstract Background Lymphovascular invasion (LVI) is a prerequisite step in breast cancer (BC) metastasis. We have previously identified wild-type isocitrate dehydrogenase 2 (IDH2) as a key putative driver of LVI. Thus, we explored the prognostic significance of IDH2 at transcriptome and protein expression levels in pre-invasive and invasive disease. Methods Utlising tissue microarrays from a large well annotated BC cohort including ductal carcinoma in situ and invasive breast cancer (IBC), IDH2 was assessed at the transcriptomic and proteomic level. The associations between clinicopathological factors including LVI status, prognosis and the expression of IDH2 were evaluated. Results In pure DCIS and IBC, high IDH2 protein expression was associated with features of aggressiveness including high nuclear grade, larger size, comedo necrosis and hormonal receptor negativity and LVI, higher grade, larger tumour size, high NPI, HER2 positivity, and hormonal receptor negativity, respectively. High expression of IDH2 either in mRNA or in protein levels was associated with poor patient’s outcome in both DCIS and IBC. Multivariate analysis revealed that IDH2 protein expression was an independent risk factor for shorter BC specific-survival. Conclusion Further functional studies to decipher the role of IDH2 and its mechanism of action as a driver of BC progression and LVI are warranted.

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RRM2 expression in different molecular subtypes of breast cancer and its prognostic significance

Diagnostic Pathology ◽

10.1186/s13000-021-01174-4 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Manar Ahmed Abdel-Rahman ◽

Mena Mahfouz ◽

Hany Onsy Habashy

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Tumour Size ◽

Prognostic Significance ◽

Disease Free Survival ◽

Tissue Microarrays ◽

Positive Lymph Node ◽

Clinicopathological Parameters ◽

Breast Cancer Patients ◽

Ribonucleoside Diphosphate Reductase

Abstract Background Breast cancer is one of the most common types of cancer. Ribonucleotide reductase (RNR) is a heterodimeric tetramer consisting of two Ribonucleoside-diphosphate reductase large subunits (RRM1) and two Ribonucleoside-diphosphate reductase small subunits (RRM2). RRM2 is the building subunit of RNR that is important for synthesis of Deoxynucleoside triphosphate (dNTP) during S phase of cell cycle during DNA replication. RRM2 is associated with poor prognosis in lung and colorectal cancer. In breast cancer, increased RRM2 protein level is strongly correlated with large tumour size, positive lymph node and relapse. In this study, we aimed to study expression of RRM2 in breast cancer and to correlate it with different clinicopathological parameters in Egyptian women. Material and methods This study was performed by investigating RRM2 protein expression in breast cancer and correlating the results with other clinicopathological variables using immunohistochemistry and tissue microarrays. Results About 77% of cases were RRM2 positive. High Ki67 was observed in cases with high RRM2 score. The majority of non-luminal cases expressed RRM2, however this was statistically insignificant. In ER positive group, RRM2 expression was associated with shorter disease free survival with borderline significance. Conclusion RRM2 protein expression can help in evaluating outcome of breast cancer patients and could be a potential therapeutic target.

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Significance of chromosome 17 polysomy in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e12002 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e12002-e12002

Author(s):

Robert W. Galamaga ◽

Rachel Mariani ◽

Imad Almanaseer ◽

Jacob D. Bitran

Keyword(s):

Breast Cancer ◽

Survival Data ◽

Copy Number ◽

Prognostic Significance ◽

Disease Free Survival ◽

Chromosome 17 ◽

Gene Copy ◽

Breast Cancers ◽

Her 2 ◽

Disease Free

e12002 Background: Human epidermal growth factor receptor 2 (HER-2) overexpression occurs in up to 30% of breast cancers and has been associated with poor clinical outcomes that have improved with advances in HER-2 directed therapy. The HER-2 gene resides on the long arm of chromosome 17 and amplification is typically assessed via immunohistochemistry or fluorescence in situ hybridization (FISH); HER-2 is interpreted as amplified, non-amplified, or equivocal. The effect and clinical impact of chromosome 17 polysomy in specimens interpreted as HER-2 non-amplified has not been well-established in breast cancer patients. This subgroup may represent a unique set of patients who may benefit from HER-2 directed therapy given the increase in HER-2 gene copy number. If tumors with polysomy 17 share biologic similarities with those positive for HER-2 amplification this may significantly influence the approach to treating these patients. In a single institution study we reviewed all breast cancer cases diagnosed in 2008 which were reported as HER-2 equivocal or non-amplified via FISH and with chromosome 17 polysomy in order to extrapolate disease-free and overall survival data within this subset. Methods: HER-2 expression via FISH from patients diagnosed with breast cancer in 2008 was reviewed. In those patients with equivocal or non-amplified HER-2 expression we selected those with chromosome 17 polysomy defined as a chromosome 17 centromere copy number of > 3 per tumor cell. A total of 9 patients were identified. Results: The median age was 74 (36-88). Median tumor size was 1.6 cm (0.7-4.9) and 8 patients (88%) had both estrogen and progesterone positive tumors. Stage distribution was as follows: stage IA: 4 (44%); stage IIA: 2 (22%); stage IIB: 2 (22%) and stage IIIA: 1 (11%). The actuarial 3 year disease free survival was 67%. Conclusions: Breast cancers with equivocal or non-amplified HER-2 expression with chromosome 17 polysomy represent a unique subset of tumors with a biology that is not well-understood. Previously published studies have yielded conflicting results regarding the prognostic significance of this genotype. Our study reflects a three year survival of 67% which suggests that these patients represent an aggressive subset.

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Co-expression of ER-beta and HER2 associated with poorer prognosis in primary breast cancer

Clinical & Investigative Medicine ◽

10.25011/cim.v32i3.6114 ◽

2009 ◽

Vol 32 (3) ◽

pp. 250 ◽

Cited By ~ 7

Author(s):

Wen-sheng Qui ◽

Lu Yue ◽

Ai-ping Ding ◽

Jian Sun ◽

Yang Yao ◽

...

Keyword(s):

Breast Cancer ◽

Cell Differentiation ◽

Primary Breast Cancer ◽

Tumour Size ◽

Univariate Analysis ◽

Growth Factor Receptor ◽

Disease Free Survival ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Er Alpha

Purpose: To assess the prognostic value of co-expression of estrogen receptor (ER)-beta and human epidermal growth factor receptor 2 (HER2) in primary breast cancer patients in China. Methods: Tumour specimens from 308 patients undergoing surgery for primary breast cancer were evaluated. Expression of ER-beta and HER-2 was investigated by the immunohistochemistry. Results: 123 patients (40%) were ER-beta positive and 58 (18.5 %) were HER2 positive. Among the 58 HER2 positive patients, 44 were ER-beta positive and 14 were ER-beta negative. ER-beta positive was associated with HER2 positive (75.9%, P=0.018) as well as ER-alpha positive (79.7%, P=0.023), poor cell differentiation (77.2% grade 2 or 3, P=0.010) and menopause age < 45 yr (55.3%, P=0.031). HER2 positive was associated with poor cell differentiation (93.1%, P=0.001), ?3cm tumour size (67.2%, P=0.011). Conclusion: Both ER-beta positive and HER2 positive status was associated with poorer overall survival (OS) by univariate analysis. In both HER2 positive and HER2 negative subgroups, ER-beta positive was associated with poorer distant disease free survival (DDFS) but not OS, which implied that ER-beta might relate to metastasis in breast cancer.

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Serum Carboxypeptidase N1 Serves as a Potential Biomarker Complementing CA15-3 for Breast Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666200703191135 ◽

2020 ◽

Vol 20 (17) ◽

pp. 2053-2065

Author(s):

Ranliang Cui ◽

Chaomin Wang ◽

Qi Zhao ◽

Yichao Wang ◽

Yueguo Li

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Critical Concentration ◽

Tumour Size ◽

Clinical Stage ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Potential Biomarker ◽

Incidence And Mortality ◽

Combined Detection

Background: The incidence and mortality of breast cancer are increasing annually. Breast cancer seriously threatens women's health and quality of life. We aimed to measure the clinical value of CPN1, a new serum marker of breast cancer and to evaluate the efficacy of CPN1 in combination with CA15-3. Methods: Seventy samples of breast cancer with lymph node metastasis, seventy-three samples of nonmetastatic breast cancer and twenty-five samples of healthy human serum were collected. Serum CA15-3 concentration was determined by Roche Elecsys, and serum CPN1 concentration was determined by ELISA. Results: In breast cancer patients, serum CPN1 concentration was positively correlated with tumour size, clinical stage and CA15-3 concentration (r = 0.376, P<0.0001). ROC curve analysis showed that the optimal critical concentration of CPN1 for breast cancer diagnosis was 32.8pg/ml. The optimal critical concentration of CPN1 in the diagnosis of metastatic breast cancer was 66.121pg/ml. CPN1 has a greater diagnostic ability for breast cancer (AUCCA15-3=0.702 vs. AUCCPN1=0.886, P<0.0001) and metastatic breast cancer (AUCCA15-3=0.629 vs. AUCCPN1=0.887, P<0.0001) than CA15-3, and the combined detection of CA15-3 and CPN1 can improve the diagnostic efficiency for breast cancer (AUCCA15-3+CPN1=0.916) and for distinguishing between metastatic and non-metastatic breast cancer (AUCCA15-3+CPN1=0.895). Conclusion: CPN1 can be used as a new tumour marker to diagnose and evaluate the invasion and metastasis of breast cancer. The combined detection of CPN1 and CA15-3 is more accurate and has a certain value in clinical application.

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Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) in Luminal Breast Cancer: A Retrospective Analysis in the Neoadjuvant Setting

Cells ◽

10.3390/cells10071685 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1685

Author(s):

Antonino Grassadonia ◽

Vincenzo Graziano ◽

Laura Iezzi ◽

Patrizia Vici ◽

Maddalena Barba ◽

...

Keyword(s):

Breast Cancer ◽

Disease Free Survival ◽

Post Treatment ◽

Neutrophil To Lymphocyte Ratio ◽

Luminal Breast Cancer ◽

Luminal A ◽

Luminal B ◽

Lymphocyte Ratio ◽

Cell Counts ◽

Pre Treatment

The neutrophil to lymphocyte ratio (NLR) is a promising predictive and prognostic factor in breast cancer. We investigated its ability to predict disease-free survival (DFS) and overall survival (OS) in patients with luminal A- or luminal B-HER2-negative breast cancer who received neoadjuvant chemotherapy (NACT). Pre-treatment complete blood cell counts from 168 consecutive patients with luminal breast cancer were evaluated to assess NLR. The study population was stratified into NLRlow or NLRhigh according to a cut-off value established by receiving operator curve (ROC) analysis. Data on additional pre- and post-treatment clinical-pathological characteristics were also collected. Kaplan–Meier curves, log-rank tests, and Cox proportional hazards models were used for statistical analyses. Patients with pre-treatment NLRlow showed a significantly shorter DFS (HR: 6.97, 95% CI: 1.65–10.55, p = 0.002) and OS (HR: 7.79, 95% CI: 1.25–15.07, p = 0.021) compared to those with NLRhigh. Non-ductal histology, luminal B subtype, and post-treatment Ki67 ≥ 14% were also associated with worse DFS (p = 0.016, p = 0.002, and p = 0.001, respectively). In a multivariate analysis, luminal B subtype, post-treatment Ki67 ≥ 14%, and NLRlow remained independent prognostic factors for DFS, while only post-treatment Ki67 ≥ 14% and NLRlow affected OS. The present study provides evidence that pre-treatment NLRlow helps identify women at higher risk of recurrence and death among patients affected by luminal breast cancer treated with NACT.

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Stromal Cell-Derived Factor 1α (SDF-1α) in Invasive Breast Cancer: Associations with Vasculo-Angiogenic Factors and Prognostic Significance

Cancers ◽

10.3390/cancers13081952 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1952

Author(s):

Elżbieta Zarychta ◽

Barbara Ruszkowska-Ciastek ◽

Kornel Bielawski ◽

Piotr Rhone

Keyword(s):

Breast Cancer ◽

Invasive Breast Cancer ◽

Stromal Cell ◽

Prognostic Significance ◽

Disease Free Survival ◽

Breast Cancer Patients ◽

Roc Curve Analysis ◽

Stromal Cell Derived Factor ◽

A Prospective Study

(1) Background: Tumour angiogenesis is critical for the progression of neoplasms. A prospective study was designed to examine the utility of stromal cell-derived factor 1α (SDF-1α) and selected vasculo-angiogenic parameters for estimating the probability of disease relapse in 84 primary, operable invasive breast cancer (IBrC) patients (40 (48%) with stage IA and 44 (52%) with stage IIA and IIB). (2) Methods: We explored the prognostic value of the plasma levels of SDF-1α, vascular endothelial growth factor A (VEGF-A), the soluble forms of VEGF receptors type 1 and 2, and the number of circulating endothelial progenitor cells (circulating EPCs) in breast cancer patients. The median follow-up duration was 58 months, with complete follow-up for the first event. (3) Results: According to ROC curve analysis, the optimal cut-off point for SDF-1α (for discriminating between patients at high and low risk of relapse) was 42 pg/mL, providing 57% sensitivity and 75% specificity. Kaplan–Meier curves for disease-free survival (DFS) showed that concentrations of SDF-1α lower than 42 pg/dL together with a VEGFR1 lower than 29.86 pg/mL were significantly associated with shorter DFS in IBrC patients (p = 0.0381). Patients with both SDF-1α lower than 42 pg/dL and a number of circulating EPCs lower than 9.68 cells/µL had significantly shorter DFS (p = 0.0138). (4) Conclusions: Our results imply the clinical usefulness of SDF-1α, sVEGFR1 and the number of circulating EPCs as prognostic markers for breast cancer in clinical settings.

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Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial

Journal of Clinical Oncology ◽

10.1200/jco.18.00440 ◽

2019 ◽

Vol 37 (2) ◽

pp. 105-114 ◽

Cited By ~ 21

Author(s):

Thomas Ruhstaller ◽

Anita Giobbie-Hurder ◽

Marco Colleoni ◽

Maj-Britt Jensen ◽

Bent Ejlertsen ◽

...

Keyword(s):

Breast Cancer ◽

Adverse Events ◽

Contralateral Breast Cancer ◽

Disease Free Survival ◽

Luminal Breast Cancer ◽

Free Survival ◽

Long Term Follow Up ◽

Disease Free

Purpose Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. Patients and Methods BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. Results Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. Conclusion Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

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Methylation of the NT5E Gene Is Associated with Poor Prognostic Factors in Breast Cancer

Diagnostics ◽

10.3390/diagnostics10110939 ◽

2020 ◽

Vol 10 (11) ◽

pp. 939

Author(s):

Young Ju Jeong ◽

Hoon Kyu Oh ◽

Hye Ryeon Choi ◽

Sung Hwan Park

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Methylation Status ◽

Prognostic Significance ◽

Disease Free Survival ◽

Receptor Expression ◽

Gene Methylation ◽

Clinicopathologic Characteristics ◽

Large Tumor ◽

The Mean

Cluster of differentiation (CD) 73, which is encoded by the NT5E gene, regulates production of immunosuppressive adenosine and is an emerging checkpoint in cancer immunotherapy. Despite the significance of CD73 in immuno-oncology, the roles of the NT5E gene methylation in breast cancer have not been well-defined yet. Therefore, we aimed to investigate the prognostic significance of the NT5E gene methylation in breast cancer. The DNA methylation status of the NT5E gene was analyzed using pyrosequencing in breast cancer tissues. In addition, the levels of inflammatory markers and lymphocyte infiltration were evaluated. The mean methylation level of the NT5E gene was significantly higher in breast cancer than in normal breast tissues. In the analysis of relevance with clinicopathologic characteristics, the mean methylation levels of the NT5E gene were significantly higher in patients with large tumor size, high histologic grade, negative estrogen receptor expression, negative Bcl-2 expression, and premenopausal women. There was no difference in disease-free survival according to the methylation status of the NT5E gene. We found that the NT5E gene methylation was related to breast cancer development and associated with poor prognostic factors in breast cancer. Our results suggest that the NT5E gene methylation has potential as an epigenetic biomarker in breast cancer.

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