Abstract
SummaryM2-tumor-associated macrophages (M2-TAMs) in the tumor microenvironment represent a prognostic indicator for poor outcome in triple-negative breast cancer (TNBC).Here we show that Prune-1 overexpression in human TNBC patients has positive correlation to lung metastasis and infiltrating M2-TAMs. Thus, we demonstrate that Prune-1 promotes lung metastasis in a genetically engineered mouse model of metastatic TNBC augmenting M2-polarization of TAMs within the tumor microenvironment. Thus, this occurs through TGF-β enhancement, IL-17F secretion, and extracellular vesicle protein content modulation.We also find murine inactivating gene variants in human TNBC patient cohorts that are involved in activation of the innate immune response, cell adhesion, apoptotic pathways, and DNA repair. Altogether, we indicate that the overexpression of Prune-1, IL-10, COL4A1, ILR1, and PDGFB, together with inactivating mutations of PDE9A, CD244, Sirpb1b, SV140, Iqca1, and PIP5K1B genes, might represent a route of metastatic lung dissemination that need future prognostic validations.
Highlights
Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers (BCs) (Neophytou et al, 2018), where the tumorigenic cells are negative for the estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2; i.e., ER, PgR, HER2–) (Rakha and Chan, 2011)
Overexpression of Prune-1 in metastatic triple-negative breast cancer (TNBC) cells enhances the canonical Transforming growth factor b (TGF-b) and Wnt signaling cascades Through interactions with its protein-binding partners (i.e., NDPK-A (Garzia et al, 2008; D’Angelo et al, 2004), GSK-3b (Kobayashi et al, 2006)), Prune-1 modulates signaling cascades, including the canonical Wnt (Carotenuto et al, 2014) and TGF-b pathways (Ferrucci et al.), which are involved in BC progression and metastasis (Pohl et al, 2017; Ding et al, 2016)
We found the highest expression of Prune-1 in the public TNBC dataset (i.e., Brown (Burstein et al, 2015), n = 198; Figures 1A and S1A, within the red dashed line), which suggested a role for Prune1 in this highly metastatic BC subgroup
Summary
Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers (BCs) (Neophytou et al, 2018), where the tumorigenic cells are negative for the estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2; i.e., ER–, PgR–, HER2–) (Rakha and Chan, 2011). TNBC is the most aggressive subtype of BCs due to its aggressive clinicopathological features, including young age at onset, large tumor size (Rakha and Chan, 2011), and greater propensity for visceral metastasis to distant sites (Lin et al, 2012). Among the metastatic patients diagnosed with TNBC, 49.3% develop metastasis in the lung (Xiao et al, 2018). Due to the absence of recognized molecular targets for therapy, TNBC patients with lung metastasis have the poorest outcome compared with those diagnosed with other metastatic BC subtypes (Xiao et al, 2018; Cancer Genome Atlas, 2012). Six distinct molecular TNBC entities have been described: two basal-like-related subgroups (basal-like 1 [BL1] and 2 [BL2]), two mesenchymal-related subgroups (mesenchymal [M], mesenchymal stem-like [MSL]), one luminal androgen receptor (LAR) group, and one immunomodulatory (IM) subgroup, with MSL and IM subtypes that are driven by tumor-associated stromal cells and tumor-infiltrating lymphocytes (TILs), respectively, in the tumor microenvironment (TME) (Lehmann et al, 2011, 2016)
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