Stromal SNAI2 Is Required for ERBB2 Breast Cancer Progression

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.
S. Castillo-Lluva was the recipient of a Ramón y Cajal research contract from the Spanish Ministry of Economy and Competitiveness (Ministerio de Economía y Competitividad; MINECO), and the work was supported by a MINECO/FEDER research grant (SAF2015-64499-R; RTI2018-094130-B-100). N. García-Sancha was partially supported by the RTI2018-094130-B-100 budget. J. Pérez-Losada was partially supported by FEDER funds, the Carlos III Health Institute (PIE14/00066), MINECO (SAF2014-56989-R, SAF2017-88854R), Castile and León (CSI234P18), the Sandra Ibarra Foundation for Solidarity against Cancer and the “We can be heroes” Foundation. N. García-Sancha is a recipient of an FPU fellowship (MINECO/FEDER). R. Corchado-Cobos, M.d.M. Sáez-Freire, and A. Blanco-Gómez were funded by fellowships from the Spanish Regional Government of Castile and León. The development of the Snai2 KO mice was supported by NIH grant R01HD034883 (to T. Gridley)