Macrophages in breast cancer: do involution macrophages account for the poor prognosis of pregnancy-associated breast cancer?
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ABSTRACT:
SUBMITTER: O'Brien J
PROVIDER: S-EPMC2693782 | biostudies-other | 2009 Jun
REPOSITORIES: biostudies-other
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Project description:Tumor-associated macrophages (TAMs) are associated with a poor outcome in breast cancer (BC), but their prognostic value in different BC subtypes has remained somewhat unclear. Here, we investigated the prognostic value of M2-like TAMs (CD163+) and all TAMs (CD68+) in a patient cohort of 278 non-metastatic BC patients, half of whom were HER2+ (n = 139). The survival endpoints investigated were overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). In the whole patient cohort (n = 278), a high CD163+ TAM count and a high CD68+ TAM count were associated with a worse outcome (p ≤ 0.023). In HER2+ BC, a high CD163+ TAM count was an independent factor for a poor prognosis across all the investigated survival endpoints (p < 0.001). The prognostic effect was evident in both the HER2+/hormone receptor-positive (p < 0.001) and HER2+/hormone receptor-negative (p ≤ 0.012) subgroups and regardless of the provision of adjuvant trastuzumab (p ≤ 0.002). In HER2-negative BC, the CD163+ TAM count was not significantly associated with survival. These results suggest that a high CD163+ TAM count predicts an inferior outcome, especially in HER2+ BC patients, and as adjuvant trastuzumab did not overcome the poor prognostic effect, combination treatments including therapies targeting the macrophage function could represent an effective therapeutic approach in HER2+ BC.
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Project description:Multi drug resistance protein 1 (MDR1) expression on tumor cells has been widely investigated in context of drug resistance. However, the role of MDR1 on the immune cell infiltrate of solid tumors remains unknown. The aim of this study was to analyze the prognostic significance of a MDR1+ immune cell infiltrate in epithelial ovarian cancer (EOC) and to identify the MDR1+ leucocyte subpopulation. MDR1 expression was analyzed by immunohistochemistry in 156 EOC samples. In addition to MDR1+ cancer cells, we detected a MDR1+ leucocyte infiltrate (high infiltrate >4 leucocytes per field of view). Correlations and survival analyses were calculated. To identify immune cell subpopulations immunofluorescence double staining was performed. The MDR1+ leucocyte infiltrate was associated with human epidermal growth factor receptor 2 (HER2) (cc = 0.258, p = 0.005) and tumor-associated mucin 1 (TA-MUC1) (cc = 0.202, p = 0.022) expression on cancer cells. A high MDR1+ leucocyte infiltrate was associated with impaired survival, especially in patients whose carcinoma showed either serous histology (median OS 28.80 vs. 50.64 months, p = 0.027, n = 91) or TA-MUC1 expression (median OS 30.60 vs. 63.36 months, p = 0.015, n = 110). Similar findings for PFS suggest an influence of MDR1+ immune cells on the development of chemoresistance. A Cox regression analysis confirmed the independency of a high MDR1+ leucocyte infiltrate as prognostic factor. M2 macrophages were identified as main part of the MDR1+ leucocyte infiltrate expressing MDR1 as well as the M2 marker CD163 and the pan-macrophage marker CD68. Infiltration of MDR1+ leucocytes, mostly M2 macrophages, is associated with poor prognosis of EOC patients. Further understanding of the interaction of M2 macrophages, MDR1 and TA-MUC1 appears to be a key aspect to overcome chemoresistance in ovarian cancer.
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Project description:Monocarboxylate transporter 1 (MCT1) participates in the transport of lactate to facilitate metabolic reprogramming during tumor progression. Tumor-associated macrophages (TAMs) are also involved in the inflammatory adaptation of the tumor microenvironment (TME). This study aimed to determine the correlation between metabolite changes and the polarization of macrophages in the TME. We demonstrated that the expression of CD163 on macrophages was significantly higher in breast cancer tissues than in normal tissues, especially in the HER2 subtype, although it was not statistically associated with recurrence-free survival (RFS). The presence of MCT1+ and CD163+ macrophages in the invasive margin was significantly correlated with decreased RFS. A significant correlation existed between MCT1 and CD163 expression in the margin, and high infiltration of MCT1+CD163+ macrophages into the margin predicted rapid progression and poor survival outcomes for breast cancer patients. These data suggested that MCT1 at least partially promoted the alternative polarization of macrophages to inhibit antitumor immunity, and blocking this interaction may be a promising method for breast cancer therapy.
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Project description:Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and the lack of specific signature makes difficult the development of targeted therapeutic strategy. We previously found that PRICKLE1, an evolutionary conserved protein acting as a regulator of vertebrate development, is upregulated in TNBC. Proteomic approaches allowed us to decipher the protein complex associated to PRICKLE1 in TNBC. Within that complex, we identified a large subset of proteins involved in the regulation of Rho-GTPase family members. We build a metagene with regulators of small G-protein activity and we found that this metagene is overexpressed in TNBC and is a poor prognosis marker. We analyzed the combination of the metagene expression and PRICKLE1 expression and identified that combined expression of ECT2 and PRICKLE1 provides a worst prognosis than PRICKLE1 expression alone in TNBC. ECT2 is a GEF for Rac1 and we showed that PRICKLE1 regulate the enzymatic activity of ECT2. Finally, we also observed that Ect2 and Prickle1 are functionally connected during evolution since both act synergistically to coordinate cellular movement during vertebrate gastrulation. Our results demonstrate the pivotal role of PRICKLE1 in TNBC and build the path for development of targeted therapeutic strategies to heal TNBC patients.
2019-10-15 | PXD011253 | Pride
Project description:BackgroundThe Arp2/3 complex is required for cell migration and invasion. The Arp2/3 complex and its activators, such as the WAVE complex, are deregulated in diverse cancers. Here we investigate the expression of Arpin, the Arp2/3 inhibitory protein that antagonises the WAVE complex.MethodsWe used qRT-PCR and reverse phase protein arrays in a patient cohort with known clinical parameters and outcome, immunofluorescence in breast biopsy cryosections and breast cancer cell lines.ResultsArpin was downregulated at the mRNA and protein levels in mammary carcinoma cells. Arpin mRNA downregulation was associated with poor metastasis-free survival (MFS) on univariate analysis (P=0.022). High expression of the NCKAP1 gene that encodes a WAVE complex subunit was also associated with poor MFS on univariate analysis (P=0.0037) and was mutually exclusive with Arpin low. Arpin low or NCKAP1 high was an independent prognosis factor on multivariate analysis (P=0.0012) and was strongly associated with poor MFS (P=0.000064).ConclusionsLoss of the Arp2/3 inhibitory protein Arpin produces a similar poor outcome in breast cancer as high expression of the NCKAP1 subunit of the Arp2/3 activatory WAVE complex.
| S-EPMC4782208 | biostudies-literature
Project description:Aims: Tumor associated macrophages (TAMs) play a critical role in the initiation and progression of breast cancer. However, their prognostic significance in the molecular subtype of basal-like breast cancer (BLBC) is poorly understood. The aim of this study was to investigate the extent and patterns of TAMs in BLBC and their associations with clinicopathological features and patient survival. Methods and Results: We evaluated TAMs in 200 cases of BLBC by immunohistochemistry using the M2 macrophage marker CD163 and the pan-macrophage marker CD68 in tumor nest and stroma, and assessed their prognostic significance. The study demonstrated that infiltration of CD163+ and CD68+ macrophages in tumor stroma was of clinical relevance in BLBC, but not those in tumor nest. Increased stromal infiltration of CD68+ or CD163+ macrophages correlated with larger tumor size, higher histological grade, higher 5-year recurrence and 5-year breast cancer mortality. Although both of CD68+ and CD163+ macrophages in tumor stroma were associated with poor recurrence-free survival (RFS) and overall survival (OS), multivariate analysis demonstrated that only CD163+ macrophage was an independent predictor of RFS and OS. Conclusions: Our results highlight the prognostic importance of TAMs' location in BLBC. CD163, a highly specific biomarker for M2 macrophages, is an independent prognostic marker for BLBC patients, and may serve as an indicator or potential target of macrophage-centred therapeutic strategies.
| S-EPMC6036715 | biostudies-other
Project description:PurposeTo identify the clinicopathological features, treatment, and prognosis of patients with breast cancer, who were diagnosed during and after pregnancy.MethodsWe searched for patients with pregnancy-associated breast cancer (PABC) using the big data query and analysis system of Peking Union Medical College Hospital from between January 1, 2013, and December 31, 2021, and matched each patient with two non-PABC patients by age at diagnosis, year at diagnosis, and tumor stage. The clinicopathologic features, treatment, and outcomes of breast cancer during pregnancy (BC-P) and breast cancer during the first-year post-partum (BC-PP) were examined retrospectively in two case-control studies.ResultsEighteen BC-P cases, 36 controls for BC-P cases, 62 BC-PP cases, and 124 controls for BC-PP cases were enrolled in our study. The expression of HER-2 and Ki-67 was higher in BC-PP cases than in its controls (P=0.01, 0.018, respectively). Patients with BC-PP were more likely to choose mastectomy than breast-conserving surgery (P=0.001). There were no significant differences in event-free survival (EFS) between patients with BC-P and BC-PP and their controls.ConclusionBC-P and BC-PP patients displayed adverse clinicopathological features in our population. However, when matched by age at diagnosis, year of diagnosis, and tumor stage, BC-P and BC-PP patients did not show inferior outcomes to controls, probably due to aggressive multimodality therapy.
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Project description:2-oxogluatrate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1) was recently revealed to be a proline hydroxylase of RPS23 for translational termination. However, OGFOD1 is nuclear, whereas translational termination occurs in the cytoplasm, raising the possibility of another function of OGFOD1 in the nucleus. In this study, we demonstrate that OGFOD1 is involved in cell cycle regulation. OGFOD1 knockdown in MDA-MB-231 breast cancer cells significantly impeded cell proliferation and resulted in the accumulation of G1 and G2/M cells by decreasing the mRNA levels of G1/S transition- and G2/M-related transcription factors and their target genes. We also confirmed that OGFOD1 is highly expressed in breast cancer tissues by bioinformatic analysis and immunohistochemistry. Thus, we propose that OGFOD1 is required for breast cancer cell proliferation and is associated with poor prognosis in breast cancer.
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Project description:Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer (n = 54) and matched controls (remained alive over similar follow-up; n = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm2, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls (p < 0.05). In multivariable regression models, MD decline (?10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm2, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.
| S-EPMC6912285 | biostudies-literature
Project description:BackgroundTriple-negative breast cancers (TNBC) are poor-prognosis tumours candidate to chemotherapy as only systemic treatment. We previously found that PRICKLE1, a prometastatic protein involved in planar cell polarity, is upregulated in TNBC. We investigated the protein complex associated with PRICKLE1 in TNBC to identify proteins possibly involved in metastatic dissemination, which might provide new prognostic and/or therapeutic targets.MethodsWe used a proteomic approach to identify protein complexes associated with PRICKLE1. The mRNA expression levels of the corresponding genes were assessed in 8982 patients with invasive primary breast cancer. We then characterised the molecular interaction between PRICKLE1 and the guanine nucleotide exchange factor ECT2. Finally, experiments in Xenopus were carried out to determine their evolutionarily conserved interaction.ResultsAmong the PRICKLE1 proteins network, we identified several small G-protein regulators. Combined analysis of the expression of PRICKLE1 and small G-protein regulators had a strong prognostic value in TNBC. Notably, the combined expression of ECT2 and PRICKLE1 provided a worst prognosis than PRICKLE1 expression alone in TNBC. PRICKLE1 regulated ECT2 activity and this interaction was evolutionary conserved.ConclusionsThis work supports the idea that an evolutionarily conserved signalling pathway required for embryogenesis and activated in cancer may represent a suitable therapeutic target.
| S-EPMC6734648 | biostudies-literature