A study of the regulation of oestrogen receptor alpha by tissue factor in breast cancer cells

Increased expression of tissue factor (TF) has been associated with invasive forms of breast cancer. In contrast, the expression of oestrogen receptor alpha (ERa) in breast cancer cells is associated with well differentiated breast tumours, with a low invasive potential. The aim of this study was to examine the influence of exogenous TF on the expression of ERa in breast cancer cells, as well as alterations in cell proliferation and invasiveness, and to explore the underlying mechanisms. Incubation of the MCF-7 and T47D breast cancer cell lines with exogenous TF resulted in decreases in the expression of ERa mRNA and protein by a mechanism requiring the interaction of TF with β1 integrin leading to the activation of the ERK1/2 pathway, but was independent of PAR1 and PAR2 activation. Furthermore, exogenous TF suppressed oestradiol-mediated cell proliferation through a pathway partly mediated through PAR2 activation, and also reversed the inhibitory influence of oestradiol on cell invasion. Exogenous TF also decreased the transcriptional activity of ERa via the classical ERE pathway through a mechanism that involved decreases in the DNA binding activity of ERa to ERE sequences, although the phosphorylation state of serine 118 within ERa was unaffected. Moreover, while TF alone was capable of downregulating the transcriptional activity of AP-1, oestradiol did not affect the transcriptional activity of AP-1. Exogenous TF was shown to bind to the surface of MCF-7 cells by direct interaction with cell surface β1 integrin which could be disrupted with polyclonal antibodies against TF or β1 integrin. Furthermore, using computer-aided analysis, a putative binding site for TF within the EGF-4 domain of β1 integrin was identified which had structural resemblance to the EGF-1 domain of FXa responsible for binding to TF. These data suggest that exogenous TF released from stromal cells interacts with breast cancer cells resulting in the downregulation of ERa which in turn leads to the loss of oestradiol-controlled proliferation and contributes to the progression of breast cancers to an invasive phenotype.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Hull

Year dc:date.issued

2008

Author dc:creator

• Collier, Mary E. W.

• Biological sciences

Language dc:language

en

Identifier

oai:hull-repository.worktribe.com:4213106

OAI identifier oai:identifier

oai:hull-repository.worktribe.com:4213106