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 phos-phorylation 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.
Original language | English |
---|---|
Pages (from-to) | 459-471 |
Number of pages | 13 |
Journal | Breast Cancer Research and Treatment |
Volume | 133 |
Issue number | 2 |
DOIs | |
State | Published - Jun 2012 |
Bibliographical note
Funding Information:Acknowledgments Financial support: MS work is supported by a Grant from the Susan G. Komen for the Cure Foundation (BCTR0600341) and ANPCyT (PICT2008-0325/Préstamo BID); EBKJ by ANPCyT (PICT 00417/Préstamo BID) and UBACyT (M003). MJB’s laboratory is supported by grants from the U.S. Department of Energy, OBER Office of Biological and Environmental Research (DE-AC02-05CH1123), a Distinguished Fellow Award and Low Dose Radiation Program and the Office of Health and Environmental Research, Health Effects Division, (03-76SF00098); by National Cancer Institute awards 5 R01CA064786, R01CA057621, U54CA126552 and U54CA112970; by U.S. Department of Defense (W81XWH0810736).
Funding
Acknowledgments Financial support: MS work is supported by a Grant from the Susan G. Komen for the Cure Foundation (BCTR0600341) and ANPCyT (PICT2008-0325/Préstamo BID); EBKJ by ANPCyT (PICT 00417/Préstamo BID) and UBACyT (M003). MJB’s laboratory is supported by grants from the U.S. Department of Energy, OBER Office of Biological and Environmental Research (DE-AC02-05CH1123), a Distinguished Fellow Award and Low Dose Radiation Program and the Office of Health and Environmental Research, Health Effects Division, (03-76SF00098); by National Cancer Institute awards 5 R01CA064786, R01CA057621, U54CA126552 and U54CA112970; by U.S. Department of Defense (W81XWH0810736).
Funders | Funder number |
---|---|
Health Effects Division | 03-76SF00098 |
Office of Health and Environmental Research | |
U.S. Department of Defense | W81XWH0810736 |
Michigan State University-U.S. Department of Energy (MSU-DOE) Plant Research Laboratory | |
National Childhood Cancer Registry – National Cancer Institute | R01CA057621, R01CA064786, U54CA112970, U54CA126552 |
Susan G. Komen for the Cure | BCTR0600341 |
Biological and Environmental Research | DE-AC02-05CH1123 |
Agencia Nacional de Promoción Científica y Tecnológica | PICT2008-0325 |
Secretaría de Ciencia y Técnica, Universidad de Buenos Aires | M003 |
Keywords
- Breast cancer
- Estrogen receptor
- Fibronectin
- Soluble stromal factors
- Tamoxifen resistance
- Tumor microenvironment
- β1 integrin
ASJC Scopus subject areas
- Oncology
- Cancer Research