CD68, CD163, and matrix metalloproteinase 9 (MMP-9) co-localization in breast tumor microenvironment predicts survival differently in ER-positive and -negative cancers View Full Text


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Article Info

DATE

2018-12

AUTHORS

Vasiliki Pelekanou, Franz Villarroel-Espindola, Kurt A. Schalper, Lajos Pusztai, David L. Rimm

ABSTRACT

BACKGROUND: The role of tumor-associated macrophages (TAMs) in the cancer immune landscape and their potential as treatment targets or modulators of response to treatment are gaining increasing interest. TAMs display high molecular and functional complexity. Therefore their objective assessment as breast cancer biomarkers is critical. The aims of this study were to objectively determine the in situ expression and significance of TAM biomarkers (CD68, CD163, and MMP-9) in breast cancer and to identify subclasses of patients who could benefit from TAM-targeting therapies. METHODS: We measured CD68, CD163, and MMP-9 protein expression in formalin-fixed paraffin-embedded tissues of breast carcinomas represented in tissue microarray format using multiplexed quantitative immunofluorescence (QIF) in two independent Yale cohorts: cohort A-n = 398, estrogen receptor-positive (ER+) and ER- cases-and the triple-negative breast cancer (TNBC)-only cohort B (n = 160). Associations between macrophage markers, ER status, and survival were assessed. Protein expression measured by QIF was compared with mRNA expression data from the METABRIC study. RESULTS: All three macrophage markers were co-expressed, displaying higher expression in ER- cancers. High pan-macrophage marker CD68 correlated with poorer overall survival (OS) only in ER- cases of cohort A (P = 0.02). High expression of CD163 protein in TAMs was associated with improved OS in ER- cases (cohort A, P = 0.03 and TNBC cohort B, P = 0.04, respectively) but not in ER+ cancers. MMP-9 protein was not individually associated with OS. High expression of MMP-9 in the CD68+/CD163+ TAMs was associated with worse OS in ER+ tumors (P <0.001) but not in ER- cancers. In the METABRIC dataset, mRNA levels followed the co-expression pattern observed in QIF but did not always show the same trend regarding OS. CONCLUSIONS: Macrophage activity markers correlate with survival differently in ER+ and ER- cancers. The association between high co-expression and co-localization of MMP-9/CD163/CD68 and poor survival in ER+ cancers suggests that these cancers may be candidates for macrophage-targeted therapies. More... »

PAGES

154

References to SciGraph publications

  • 2016-10. Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: results of the ring studies of the international immuno-oncology biomarker working group in MODERN PATHOLOGY
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  • 2016-01. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis in NATURE IMMUNOLOGY
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  • 2012-12. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients in BMC CANCER
  • 2014-12. Tumor-infiltrating immune cell profiles and their change after neoadjuvant chemotherapy predict response and prognosis of breast cancer in BREAST CANCER RESEARCH
  • 2016-12. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy in NPJ BREAST CANCER
  • 2014-12. MMP-9 expression varies according to molecular subtypes of breast cancer in BMC CANCER
  • 2016-05-10. The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes in NATURE COMMUNICATIONS
  • 2012-12. The presence of sinusoidal CD163+ macrophages in lymph nodes is associated with favorable nodal status in patients with breast cancer in VIRCHOWS ARCHIV
  • 2015-12. Human breast cancer cells educate macrophages toward the M2 activation status in BREAST CANCER RESEARCH
  • 2012-06. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups in NATURE
  • 2017-01-24. Tumour-associated macrophages as treatment targets in oncology in NATURE REVIEWS CLINICAL ONCOLOGY
  • Identifiers

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    http://scigraph.springernature.com/pub.10.1186/s13058-018-1076-x

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    http://dx.doi.org/10.1186/s13058-018-1076-x

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1110710956

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30558648


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