Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

Abstract

SNAI2 overexpression appears to be associated with poor prognosis in breast cancer, yet it remains unclear in which breast cancer subtypes this occurs. Here we show that excess SNAI2 is associated with a poor prognosis of luminal B HER2+/ERBB2+ breast cancers in which SNAI2 expression in the stroma but not the epithelium correlates with tumor proliferation. To determine how stromal SNAI2 might influence HER2+ tumor behavior, Snai2-deficient mice were crossed with a mouse line carrying the ErbB2/Neu protooncogene to generate HER2+/ERBB2+ breast cancer. Tumors generated in this model expressed SNAI2 in the stroma but not the epithelium, allowing for the role of stromal SNAI2 to be studied without interference from the epithelial compartment. The absence of SNAI2 in the stroma of HER2+/ERBB2+ tumors is associated with: (i) lower levels of cyclin D1 (CCND1) and reduced tumor epithelium proliferation; (ii) higher levels of AKT and a lower incidence of metastasis; (iii) lower levels of angiopoietin-2 (ANGPT2), and more necrosis. Together, these results indicate that the loss of SNAI2 in cancer-associated fibroblasts limits the production of some cytokines, which influences AKT/ERK tumor signaling and subsequent proliferative and metastatic capacity of ERBB2+ breast cancer cells. Accordingly, SNAI2 expression in the stroma enhanced the tumorigenicity of luminal B HER2+/ERBB2+ breast cancers. This work emphasizes the importance of stromal SNAI2 in breast cancer progression and patients' prognosis. Significance: Stromal SNAI2 expression enhances the tumorigenicity of luminal B HER2+ breast cancers and can identify a subset of patients with poor prognosis, making SNAI2 a potential therapeutic target for this disease.

Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

“…The roles of TGF-β signaling in CAFs have been demonstrated in more detail in breast cancer models, in which TGF-β and SDF1 are part of two autocrine and cross-talking signaling loops that drive myofibroblast/CAF development at the invasive front ( Kojima et al, 2010 ; Yu et al, 2014 ). Increased expression of the TGF-β target SNAI1 in fibroblasts leads to increased SDF-1 secretion ( Blanco-Gómez et al, 2020 ). The CAF-secreted TGF-β and SDF-1 promote angiogenesis by recruiting endothelial progenitor cells, and increase growth and EMT of tumor cells ( Orimo et al, 2005 ; Yu et al, 2014 ; Matsumura et al, 2019 ).…”

Single-nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma

“…35 Another highly expressed gene in CAFs, SNAI2 (Slug), a snail-related zinc-finger transcription factor, may inhibit apoptosis and promote cancer progression. 36,37 Several common growth factors such as TGFB1 (transforming growth factor beta 1), EGF (epidermal growth factor), and VEGFA (vascular endothelial growth factor A) were also expressed by CAFs ( Figure 4D ). Moreover, the upregulation of LSD1 (histone lysine demethylase 1) in CAFs might inhibit the IFN activation to evade immune attack.…”

“…CXCL6 (C-X-C motif chemokine ligand 6), though mainly related to immune response, was reported to promote the growth and metastasis of esophageal squamous cell carcinoma 39 (Figure 5D). Another highly expressed gene in CAFs, SNAI2 (Slug), a snail-related zinc-finger transcription factor, may inhibit apoptosis and promote cancer progression 40,41 . Several common growth factors such as TGFB1 (transforming growth factor beta 1), EGF (epidermal growth factor), and VEGFA (vascular endothelial growth factor A) were also expressed by CAFs (Figure 5D).…”

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

“…TGF-β signaling plays a key role in CAFs as demonstrated in more detail in breast cancer models; in fact, TGF-β and SDF1 take part in two autocrine and cross-talking signaling loops that are involved in myofibroblast/CAF transition [ 20 , 21 ]. High levels of TGF-β target SNAI1 in fibroblasts induce an increase of SDF-1 secretion [ 22 ]. CAFs secrete TGF-β and SDF-1 by promoting angiogenesis and stimulating cell proliferation and EMT [ 23 ].…”