Infiltrating mast cell-mediated stimulation of estrogen receptor activity in breast cancer cells promotes the luminal phenotype
| Autor: | Laura Botti, Maria Teresa Majorini, Claudio Tripodo, Alice Rigoni, Mario P. Colombo, Valeria Cancila, Claudia Chiodoni, Loris De Cecco, Daniele Lecis, Enrico Fontanella, Elena Jachetti, Matteo Dugo, Tiziana Triulzi, Elda Tagliabue |
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| Přispěvatelé: | Majorini, Maria Teresa, Cancila, Valeria, Rigoni, Alice, Botti, Laura, Dugo, Matteo, Triulzi, Tiziana, De Cecco, Lori, Fontanella, Enrico, Jachetti, Elena, Tagliabue, Elda, Chiodoni, Claudia, Tripodo, Claudio, Colombo, Mario P, Lecis, Daniele |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research Receptor ErbB-2 Estrogen receptor Breast Neoplasms Mice Transgenic Cell Communication Cell Growth Processes Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Immune system Cell Line Tumor medicine Animals Humans Mast Cells Neoplasm Metastasis skin and connective tissue diseases Estrogen receptor activity Mice Inbred BALB C business.industry Mammary Neoplasms Experimental Cancer Proto-Oncogene Proteins c-met medicine.disease Mast cell Phenotype ErbB Receptors Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Receptors Estrogen Oncology 030220 oncology & carcinogenesis Cancer research Female business mast cell estrogen receptor breast cancer luminal phenotype Estrogen receptor alpha |
| Popis: | 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. Significance: Mast cells impact breast cancer outcome by directly affecting the phenotype of tumor cells through stimulation of the estrogen receptor pathway. |
| Databáze: | OpenAIRE |
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