title: The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through β1 integrin.
abstract: Tamoxifen resistance has been largely attributed to genetic alterations in the epithelial tumor cells themselves, such as overexpression of HER-2/Neu. However, in the clinic, only about 15-20% of cases of HER-2/Neu amplification has actually been correlated to the acquisition of endocrine resistance, suggesting that other mechanisms must be involved as well. Using the epithelial LM05-E and the fibroblastic LM05-F cell lines, derived from the estrogen dependent spontaneous M05 mouse mammary tumor, as well as MCF-7 cells, we analyzed whether soluble stromal factors or extracellular matrix components protected against tamoxifen induced cell death. Involvement of signaling pathways was determined by using specific inhibitors and western blot, and phosphorylation of the estrogen receptor alpha by western blot and immunofluorescence. Soluble factors produced by the fibroblastic cells protect the epithelial tumor cells from tamoxifen-induced cell death through a mechanism that involves EGFR and matrix metalloproteinases upstream of PI3K/AKT. Exogenous fibronectin by itself confers endocrine resistance through interaction with β1 integrin and activation of PI3K/AKT and MAPK/ERK 1/2 pathways. The conferred resistance is reversed by blocking β1 integrin. We show also that treatment with both conditioned medium and fibronectin leads to the phosphorylation of the estrogen receptor at serine-118, suggesting stromal factors as modulators of ER activity. Our results show that the tumor microenvironment can modulate tamoxifen resistance, providing an alternative explanation for why patients become refractory to hormone-therapy.
authors.affiliation: Área de Investigaciones, Instituto de Oncología Ángel H. Roffo, Buenos Aires, Argentina.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Pontiggia
authors.forename: Rocio
authors.initials: R
authors.lastname: Sampayo
authors.forename: Diego
authors.initials: D
authors.lastname: Raffo
authors.forename: Andrea
authors.initials: A
authors.lastname: Motter
authors.forename: Ren
authors.initials: R
authors.lastname: Xu
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
authors.forename: Elisa Bal de Kier
authors.initials: EB
authors.lastname: Joffé
authors.forename: Marina
authors.initials: M
authors.lastname: Simian
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*; D059016:Tumor Microenvironment
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D005353:Fibronectins; D019012:Integrin beta1; D013629:Tamoxifen; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020782:Matrix Metalloproteinases