Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome.
ABSTRACT Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages-proliferating macrophages (promacs)-with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P = 0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions.
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ABSTRACT: It has long been accepted that modern reproductive patterns are likely contributors to breast cancer susceptibility because of their influence on hormones such as estrogen and the importance of these hormones in breast cancer. We conducted a meta analysis to asses whether this 'evolutionary mismatch hypothesis' can explain susceptibility to both estrogen receptor positive (ER-positive) and estrogen receptor negative (ER-negative) cancer. Our meta analysis includes a total of 33 studies and examines parity, age of first birth and age of menarche broken down by estrogen receptor status. We found that modern reproductive patterns are more closely linked to ER-positive than ER-negative breast cancer. Thus, the evolutionary mismatch hypothesis for breast cancer can account for ER-positive breast cancer susceptibility but not ER-negative breast cancer.11/2014; DOI:10.1093/emph/eou028
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ABSTRACT: The development of cancer has been an extensively researched topic over the past few decades. Although greatstrides have been made in cancer prevention, diagnosis,and treatment, there is still much to be learned about cancer'smicro-environmental mechanisms that contribute tocancer formation and aggressiveness. Macrophages, lymphocy teswhich originate from monocytes, are involved inthe inflammatory response and often dispersed to areas ofinfection to fight harmful antigens and mutated cells intissues. Macrophages have a plethora of roles includingtissue development and repair, immune system functions,and inflammation. We discuss various pathways by whichmacrophages get activated, various approaches that canregulate the function of macrophages, and how these approachescan be helpful in developing new cancer therapies.
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ABSTRACT: Introduction: Overall survival of early-stage breast cancer (BC) patients is similar for those who undergo breast conserving therapy (BCT) and mastectomy, however, 10-15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with BC subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk. Methods: We utilized two independent data sets to study gene expression data in cancer-adjacent tissue from invasive BC patients. Complementary in vitro cocultures were used to study cell-cell communication between fibroblasts and specific BC subtypes. Results: Our results suggest that intrinsic tumor subtypes are reflected in histologically-normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple negative (Claudin-low or Basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. While such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, while triple negative BCs are associated with upregulated immune response genes, Luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues. Conclusions: Specific characteristics of BCs are reflected in the surrounding histologically-normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences. Impact: Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk. Copyright © 2014, American Association for Cancer Research.Cancer Epidemiology Biomarkers & Prevention 12/2014; 24(2). DOI:10.1158/1055-9965.EPI-14-0934 · 4.32 Impact Factor