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

Osvaldo Pontiggia, Rocio Sampayo, Diego Raffo, Andrea Motter, Ren Xu, Mina J. Bissell, Elisa Bal De Kier Joffé, Marina Simian

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

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 languageEnglish
Pages (from-to)459-471
Number of pages13
JournalBreast Cancer Research and Treatment
Volume133
Issue number2
DOIs
StatePublished - 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).

Keywords

  • Breast cancer
  • Estrogen receptor
  • Fibronectin
  • Soluble stromal factors
  • Tamoxifen resistance
  • Tumor microenvironment
  • β1 integrin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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