Estrogen Stimulation of Cell Migration Involves Multiple Signaling Pathway Interactions

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.

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

“…In contrast to the AR, PXN had no effect on ERα nuclear localization in the same primary GCs and in MCF7 breast cancer cells. Previously, PXN was implicated as a regulator of nongenomic estrogen effects in breast cancer cells (24), although transcription was not examined (25). Our data confirm that estradiol rapidly triggers serine phosphorylation of PXN and subsequent nuclear localization in granulosa and breast cancer cells.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Many of the kinases activated by ERα extra-nuclear signaling are implicated in breast cancer metastasis. For example, ERK and Akt phosphorylation play important roles in breast cancer cell migration [86]. Src and ILK1 kinases play critical roles in the invasion and metastasis of breast cancer cells [87,88].…”

Postnatal exposure to low-dose decabromodiphenyl ether adversely affects mouse testes by increasing thyrosine phosphorylation level of cortactin

“…SRC is considered to regulate CTTN phosphorylation (Ammer and Weed, 2008). Given that estrogen activates SRC and ERK (Li et al, 2010;Jeng and Watson, 2011), and decaBDE can act as estrogenic effect (Tseng et al, 2008), decaBDE may activate SRC and p44/42 ERK in mouse testes. However, the present study did not show the SRC activation, just the reduction of SRC expression level.…”