Author(s): Eileen M. McNerney1 and Sergio A. Onate1,2
Prostate cancer progression to bone metastasis is an early event that remains dormant when the androgen ratio to estrogen is high. Only 40% of patients with bone metastasis and skeletal involvement survive past the first year. During andropause, changes in hormone ratios and nuclear receptor coregulator expression, in conjunction with crosstalk with fibroblast growth factors and bone stroma signaling pathways, reactivate the early metastasis. This review will provide insights into how this interplay induces changes in the osteolytic microenvironment to promote prostate cancer metastasis to the bone. While both AR and ER induce changes in the osteolytic microenvironment to promote bone metastasis, it is ERα overexpression that stimulates osteoblast differentiation, proliferation, osteoclast-mediated bone resorption, and the release of bone matrix factors. Loss of ERβ1 enhances VEGF expression and tumor cell survival through stimulation of osteoblast differentiation. Aberrant expression of FGFs and FGF receptors (FGFRs) initiates MAPK, PI3K, and PLCγ pathways, resulting in proliferation, dedifferentiation, angiogenesis and survival. The paracrine action of FGF10 may be required for bone metastasis reactivation due to interaction with bone stromal cells when E2/T ratio increases. This ratio change provides a potential mechanism for estrogen signal activation when prostate cancer cells express ERα in the presence of bone stromal cells, resulting in ERα predominance over the AR activity due to changes in coactivator/corepressor recruitment by ERα when circulating androgens are reduced during hormonal deprivation therapies.