Role of estrogen receptor signaling in breast cancer metastasis

Abstract

Metastatic breast cancer is a life-threatening stage of cancer and is the leading cause of death in advanced breast cancer patients. Estrogen signaling and the estrogen receptor (ER) are implicated in breast cancer progression, and the majority of the human breast cancers start out as estrogen dependent. Accumulating evidence suggests that ER signaling is complex, involving coregulatory proteins and extranuclear actions. ER-coregualtory proteins are tightly regulated under normal conditions with miss expression primarily reported in cancer. Deregulation of ER coregualtors or ER extranuclear signaling has potential to promote metastasis in ER-positive breast cancer cells. This review summarizes the emerging role of ER signaling in promoting metastasis of breast cancer cells, discusses the molecular mechanisms by which ER signaling contributes to metastasis, and explores possible therapeutic targets to block ER-driven metastasis.

Figure 1

ER-extranuclear signaling promotes actin reorganization via ER coregulator PELP1. (a) MCF7 shRNA vector control and MCF7-PELP1-shRNA cells were cultured in 5% DCC serum containing medium treated with or without estrogen dendrimers (EDC). The activation of signaling pathways was analyzed by Western blotting of total protein lysates with phospho-specific antibodies. (b) MCF7 cells were treated with FITC-labeled EDC and localization of EDC was analyzed by confocal microscopy. Green; EDC; Blue, DAPI. (c) MCF7 or MCF7-PELP1-shRNA cells were treated either with E2 or EDC and the F-actin status was analyzed by phalloidin staining and visualized by confocal microscopy. (d) Schematic representation of estrogen-mediated extranuclear signaling. Adapted from [10].

Figure 2

Schematic representation of hormonal regulation of metastasis. ERα-mediated signaling involves nuclear as well as extranuclear actions and growth factor signaling cross talk. Estrogen signaling has the potential to activate extranuclear signaling that activates several kinase cascades, which have potential to alter cytoskeleton, EMT and enhance cell migration. Deregulation of ERα-mediated signaling crosstalk will have implications in estrogen-mediated tumor progression to metastasis.