The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through β1 integrin

• Published in: Breast cancer research and treatment Vol. 133; no. 2; pp. 459 - 471
• Main Authors: Pontiggia, Osvaldo, Sampayo, Rocio, Raffo, Diego, Motter, Andrea, Xu, Ren, Bissell, Mina J., de Kier Joffé, Elisa Bal, Simian, Marina
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2012; Springer
• Subjects: Analysis; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Breast cancer; Breast Neoplasms - metabolism; Cell Line, Tumor; Drug Resistance, Neoplasm; Epithelial Cells - metabolism; Estrogen; Estrogen Receptor alpha - metabolism; Female; Fibroblasts - metabolism; Fibronectins; Fibronectins - metabolism; Gynecology. Andrology. Obstetrics; Humans; Integrin beta1 - metabolism; Integrins; Mammary gland diseases; Matrix Metalloproteinases - metabolism; Medical sciences; Medicine; Medicine & Public Health; Models, Biological; Oncology; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Preclinical Study; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Epidermal Growth Factor - metabolism; Tamoxifen; Tamoxifen - pharmacology; Tumor Microenvironment; Tumors; Estrogen receptor; Soluble stromal factors; Tumor microenvironment; β1 integrin; Tamoxifen resistance; Breast cancer; Fibronectin; Antineoplastic agent; Breast disease; Soluble factor; Antiestrogen; Cell microenvironment; Cell adhesion molecule; Stroma; Antihormone; Malignant tumor; Tamoxifene; Resistance; Mammary gland diseases; Selective estrogen receptor modulator; Non steroid compound; Cancer; Hormonal receptor
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-011-1766-x

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.