American Association for Cancer Research
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Figure S2 from Infiltrating Mast Cell–Mediated Stimulation of Estrogen Receptor Activity in Breast Cancer Cells Promotes the Luminal Phenotype

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journal contribution
posted on 2023-03-31, 03:03 authored by Maria Teresa Majorini, Valeria Cancila, Alice Rigoni, Laura Botti, Matteo Dugo, Tiziana Triulzi, Loris De Cecco, Enrico Fontanella, Elena Jachetti, Elda Tagliabue, Claudia Chiodoni, Claudio Tripodo, Mario P. Colombo, Daniele Lecis

Heatmap showing genes belonging to the leading edge lists of at least four gene sets of Figure 6F. Leading edge genes drives the significance of the gene sets. The color scale of the heatmap represents the fold change of the gene in the comparison of PyMT B6 versus PyMT Wsh mice. The color bar at the top of the heatmap represents the Spearman's correlation coefficient of the gene with CIBERSORT MC abundance in METABRIC dataset. (B) ER levels in tumors collected from 4 PyMT B6 and 4 PyMT Wsh mice.


Associazione Italiana per la Ricerca sul Cancro



Tumor growth and development is determined by both cancer cell–autonomous and microenvironmental mechanisms, including the contribution of infiltrating immune cells. Because the role of mast cells (MC) in this process is poorly characterized and even controversial, we investigated their part in breast cancer. Crossing C57BL/6 MMTV-PyMT mice, which spontaneously develop mammary carcinomas, with MC-deficient C57BL/6-KitW-sh/W-sh (Wsh) mice, showed that MCs promote tumor growth and prevent the development of basal CK5-positive areas in favor of a luminal gene program. When cocultured with breast cancer cells in vitro, MCs hindered activation of cMET, a master regulator of the basal program, and simultaneously promoted expression and activation of estrogen receptor (ESR1/ER) and its target genes (PGR, KRT8/CK8, BCL2), which are all luminal markers. Moreover, MCs reduced ERBB2/HER2 levels, whose inhibition further increased ESR1 expression. In vivo and in silico analysis of patients with breast cancer revealed a direct correlation between MC density and ESR1 expression. In mice engrafted with HER2-positive breast cancer tumors, coinjection of MCs increased tumor engraftment and outgrowth, supporting the link between MCs and increased risk of relapse in patients with breast cancer. Together, our findings support the notion that MCs influence the phenotype of breast cancer cells by stimulating a luminal phenotype and ultimately modifying the outcome of the disease. Mast cells impact breast cancer outcome by directly affecting the phenotype of tumor cells through stimulation of the estrogen receptor pathway.

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