Abstract:
:Hormone-dependent breast cancers respond to inhibitors of estrogen synthesis or action with tumor regression and with a reduction of new metastases. The mechanisms underlying the effects of estrogen on metastasis likely differ from those on tumor regression. Cell migration is a key first step in the metastatic process. Based on our prior work and other published data, we designed and tested a working model that suggested that estrogen receptor α, epidermal growth factor receptor, focal adhesion kinase (FAK), paxillin, phosphatidylinositol 3 kinase, p60 Src tyrosine kinase (c-Src), c-Jun N-terminal kinase, and MAPK interact to facilitate estradiol (E(2))-induced cell migration. Accordingly, we examined the effect of E(2) on activation of these pathways and demonstrated mechanistic effects by blocking each component and assessing cell migration as a biologic endpoint. Initial studies validated a robust cell migration assay characterized by highly reproducible, dose-dependent responses to E(2). Examining various mechanisms involved in migration, we showed that E(2) induced activation of c-Src, FAK, and paxillin with early peaks within 5-30 min and later peaks at 24 h. ERK and protein kinase B phosphorylation exhibited only early peaks. Blockade of various steps in these signaling pathways with use of small interfering RNA or specific inhibitors demonstrated mechanistic effects of these signaling molecules on cell migration. Our results suggest that the effects of E(2) on cell migration involve multiple, interacting signaling pathways. Important effects are mediated by the MAPK, phosphatidylinositol 3 kinase, and c-Jun N-terminal kinase pathways and use FAK, paxillin, and c-Src for activation. Each pathway represents a potential target for blocking cell migration and metastasis of breast cancer cells.
journal_name
Endocrinologyjournal_title
Endocrinologyauthors
Li Y,Wang JP,Santen RJ,Kim TH,Park H,Fan P,Yue Wdoi
10.1210/en.2009-1506subject
Has Abstractpub_date
2010-11-01 00:00:00pages
5146-56issue
11eissn
0013-7227issn
1945-7170pii
en.2009-1506journal_volume
151pub_type
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