Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression.
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ABSTRACT:
SUBMITTER: Pellegrino B
PROVIDER: S-EPMC8249273 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The fact that 20-40% of all breast cancer (BC) patients develop recurrence when 5 year survival is 90% strongly suggests that late recurrence, i.e. more than 5 years after diagnosis, is the remaining challenge to decrease the absolute number of BC deaths. Better understanding late recurrence is an essential first step to address this issue. We hypothesized that primary tumors with a distinctive tumor immune microenvironment will develop late recurrence. Accordingly, we evaluated the relationship between the timing of cancer recurrence, clinical factors, gene expression profiles, and immune status utilizing two published large cohorts. 308 primary BCs in TCGA were analyzed and categorized as: recurrence ≤2 years (Early, n = 49), between 2-5 years (Mid, n = 54), recurrence >5 years (Late, n = 20), and no recurrence >5 years (Survivors, n = 185). 1,727 primary BCs in METABRIC were analyzed and categorized similarly: Early, n = 170; distant (D), n = 19; local (L), Mid, n = 213; D, n = 21; L, Late, n = 199; D, n = 57, L, and Survivors, n = 1048. Utilizing pre-ranked GSEA, we showed that primary tumors with Survivors were associated with anti-cancer signaling such as INF-α/-γ response and TNF-α signaling, compared with all recurrence groups in pre-ranked GSEA. Furtherrmore, we found that host defense immunity (leukocyte fraction, lymphocyte infiltration, and macrophage fractions) was decreased in primary tumors with Late recurrence compared with Survivors. Utilizing the CIBERSORT algorithm, we showed anti-cancer lymphocytes, memory CD4+ T cells and γδT cells, were significantly lower, and pro-cancerous regulatory T cells were significantly higher in Late tumors compared with Survivors. In agreement, cytolytic activity score that assesses immune cell cytolytic activity was significantly lower in Late compared with Survivors. We demonstrated that not only host defense immunity, but also pro-cancerous immune cells and immune cell cytolytic activity in primary BC was associated with late recurrence.
| S-EPMC6858361 | biostudies-literature
Project description:Secreted frizzled related protein 1 (SFRP1) functions as an important inhibitor of the Wnt pathway and is a known tumor suppressor gene, which is epigenetically silenced in a variety of tumors e.g. in breast cancer. However, it is still unclear how SFRP1 exactly affects the Wnt pathway. Our aim was to decipher SFRP1 involvement in biochemical signaling in dependency of different breast cancer subtypes and to identify novel SFRP1-regulated genes. We generated SFRP1 over-expressing in vitro breast cancer models, reflecting the two major subtypes by using basal-like BT20 and luminal-like HER2-positive SKBR3 cells. DNA microarray expression profiling of these models revealed that SFRP1 expression potentially modulates Bone morphogenetic protein- and Smoothened signaling (p<0.01), in addition to the known impact on Wnt signaling. Importantly, further statistical analysis revealed that in dependency of the cancer subtype model SFRP1 may affect the canonical and non-canonical Wnt pathway (p<0.01), respectively. While SFRP1 re-expression generally mediated distinct patterns of transcriptionally induced or repressed genes in BT20 and SKBR3 cells, brain derived neurotrophic factor (BDNF) was identified as a SFRP1 induced gene in both cell lines. Although BDNF has been postulated as a putative oncogene, the co-regulation with SFRP1 indicates a potential suppressive function in breast cancer. Indeed, a positive correlation between SFRP1 and BDNF protein expression could be shown (p<0.001) in primary breast cancer samples. Moreover, TCGA dataset based analysis clearly underscores that BDNF mRNA is down-regulated in primary breast cancer samples predicting a poor prognosis of these patients. In line, we functionally provide evidence that stable BDNF re-expression in basal-like BT20 breast cancer cells blocks tumor cell proliferation. Hence, our results suggest that BDNF might rather mediate suppressive than promoting function in human breast cancer whose mode of action should be addressed in future studies.
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Project description:Background: Sirtuin 7 (SIRT7), a protein-coding gene whose abnormal expression and function are associated with carcinogenesis. However, the prognosis of SIRT7 in different breast cancer subtypes and its correlation with tumor-infiltrating lymphocytes remain unclear. Methods: The expression and survival data of SIRT7 in patients with breast cancer were analyzed using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interaction Analysis (GEPIA), The Human Protein Atlas (HPA), UALCAN, Breast Cancer Gene-Expression Miner (BC-GenExMiner), and Kaplan-Meier plotter databases. Also, the expression correlations between SIRT7 and immune infiltration gene markers were analyzed using TIMER and further verified the results using immunohistochemistry. Results: SIRT7 exhibited higher expression levels in breast cancer tissues than the adjacent normal tissues. SIRT7 expression was significantly correlated with sample type, subclass, cancer stage, menopause status, age, nodal status, estrogen receptor (ER), progesterone receptor (PR), and triple-negative status. High SIRT7 expression was associated with poor prognosis in breast cancer-luminal A [overall survival (OS): hazard ratio (HR) = 1.54, p = 1.70e-02; distant metastasis-free survival (DMFS): HR = 1.56, p = 2.60e-03]. Moreover, the expression of SIRT7 was positively correlated with the expression of IRF5 (M1 macrophages marker, r = 0.165, p = 1.13e-04) and PD1 (T cell exhaustion marker, r = 0.134, p = 1.74e-03). These results suggested that the expression of SIRT7 was related to M1 macrophages and T cell exhaustion infiltration in breast cancer-luminal. Conclusions: These findings demonstrate that the high expression of SIRT7 indicates poor prognosis in breast cancer as well as increased immune infiltration levels of M1 macrophages and T cell exhaustion in breast cancer-luminal. Thus, SIRT7 may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in breast cancer-luminal.
| S-EPMC7247806 | biostudies-literature
Project description:ImportancePatients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood.ObjectiveTo compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype.Design, setting, and participantsSecondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018.InterventionsPatients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy.Main outcomes and measuresDistant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics.ResultsIn the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59).Conclusions and relevancePatients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.
| S-EPMC6692699 | biostudies-literature
Project description:BackgroundUnlike estrogen receptor (ER)-negative breast cancer, ER-positive breast cancer outcome is less influenced by lymphocyte content, indicating the presence of immune tolerance mechanisms that may be specific to this disease subset.MethodsA supervised analysis of microarray data from the ACOSOG Z1031 (Alliance) neoadjuvant aromatase inhibitor (AI) trial identified upregulated genes in Luminal (Lum) B breast cancers that correlated with AI-resistant tumor proliferation (percentage of Ki67-positive cancer nuclei, Pearson r > 0.4) (33 cases Ki67 > 10% on AI) vs LumB breast cancers that were more AI sensitive (33 cases Ki67 < 10% on AI). Overrepresentation analysis was performed using WebGestalt. All statistical tests were two-sided.ResultsThirty candidate genes positively correlated (r ≥ 0.4) with AI-resistant proliferation in LumB and were upregulated greater than twofold. Gene ontologies identified that the targetable immune checkpoint (IC) components IDO1, LAG3, and PD1 were overrepresented resistance candidates (P ≤ .001). High IDO1 mRNA was associated with poor prognosis in LumB disease (Molecular Taxonomy of Breast Cancer International Consortium, hazard ratio = 1.43, 95% confidence interval = 1.04 to 1.98, P = .03). IDO1 also statistically significantly correlated with STAT1 at protein level in LumB disease (Pearson r = 0.74). As a composite immune tolerance signature, expression of IFN-γ/STAT1 pathway components was associated with higher baseline Ki67, lower estrogen, and progesterone receptor mRNA levels and worse disease-specific survival (P = .002). In a tissue microarray analysis, IDO1 was observed in stromal cells and tumor-associated macrophages, with a higher incidence in LumB cases. Furthermore, IDO1 expression was associated with a macrophage mRNA signature (M1 by CIBERSORT Pearson r = 0.62 ) and by tissue microarray analysis.ConclusionsTargetable IC components are upregulated in the majority of endocrine therapy-resistant LumB cases. Our findings provide rationale for IC inhibition in poor-outcome ER-positive breast cancer.
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