Abstract
None of the clinically relevant gene expression signatures available for breast cancer were specifically developed to capture the influence of the microenvironment on tumor cells. Here, we attempted to build subtype‐specific signatures derived from an in vitro model reproducing tumor cell modifications after interaction with activated or normal stromal cells. Gene expression signatures derived from HER2+, luminal, and basal breast cancer cell lines (treated by normal fibroblasts or cancer‐associated fibroblasts conditioned media) were evaluated in clinical tumors by in silico analysis on published gene expression profiles (GEPs). Patients were classified as microenvironment‐positive (μENV+ve), that is, with tumors showing molecular profiles suggesting activation by the stroma, or microenvironment‐negative (μENV−ve) based on correlation of their tumors' GEP with the respective subtype‐specific signature. Patients with estrogen receptor alpha (ER)+/HER2−/μENV+ve tumors were characterized by 2.5‐fold higher risk of developing distant metastases (HR = 2.546; 95% CI: 1.751–3.701, P = 9.84E‐07), while μENV status did not affect, or only suggested the risk of distant metastases, in women with HER2+ (HR = 1.541; 95% CI: 0.788–3.012, P = 0.206) or ER‐/HER2− tumors (HR = 1.894; 95% CI: 0.938–3.824; P = 0.0747), respectively. In ER+/HER2− tumors, the μENV status remained significantly associated with metastatic progression (HR = 2.098; CI: 1.214–3.624; P = 0.00791) in multivariable analysis including size, age, and Genomic Grade Index. Validity of our in vitro model was also supported by in vitro biological endpoints such as cell growth (MTT assay) and migration/invasion (Transwell assay). In vitro‐derived gene signatures tracing the bidirectional interaction with cancer activated fibroblasts are subtype‐specific and add independent prognostic information to classical prognostic variables in women with ER+/HER2− tumors.
Highlights
Breast cancer (BC) is the most frequently diagnosed malignancy and the leading cause of cancer-related death in women after lung cancer (Siegel et al, 2016)
The role of the microenvironment in modulating tumor progression was studied in breast cancer cell lines (BCCLs) belonging to different subtypes after paracrine interaction with human fibroblast cell line (NAF) and cancer-associated fibroblast (CAF)
Genes modulated by CAFs were used to derive three subtype-specific gene signatures, which were tested in public gene expression datasets of primary tumors for their association with clinical outcome
Summary
Breast cancer (BC) is the most frequently diagnosed malignancy and the leading cause of cancer-related death in women after lung cancer (Siegel et al, 2016). The behavior of tumor cells depends on their intrinsic features and on the interaction with the microenvironment composed by the basement membrane and the surrounding stroma, which is predominantly constituted by fibroblasts (Buchsbaum and Oh, 2016; Cunha, 1994; Donnarumma et al, 2017; Howlett and Bissell, 1993; Soysal et al, 2015), and contains different populations of immune cells Depending on their proximity to the tumor cells, fibroblasts undergo phenotypic and functional modifications becoming ‘activated myofibroblasts’ (CAFs). This creates a sustained fibrosis and wound healing response leading to a desmoplastic reaction which is frequently observed in advanced breast carcinomas (Dvorak et al, 1981; Luo et al, 2015). Fibroblasts and their activation represent a considerable part of the host reaction in response to the local damage caused by the emerging cancer cells (Casbas-Hernandez et al, 2011; Kalluri, 2016)
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