Abstract
Abstract Prostate cancer is the second leading cause of cancer related death in men in the US. The skeleton is the most common site for prostate cancer metastasis, which often results in osteoblastic lesions. Transforming growth factor-beta (TGFβ), which is a multifunctional cytokine, is important for the regulation of bone mass and matrix properties. Our group has recently shown that TGFβ signaling helps in promoting osteoblastic tumor growth by a novel human prostate cancer cell line, PacMetUT1. However, the mechanism by which prostate cancer cells metastasize to bone and how they induce formation of osteoblastic lesions remains to be intensively investigated. Bone cells such as osteoblasts express aromatase, which is the enzyme required for estrogen biosynthesis in humans. Recent data further implicates an aberrant aromatase expression and estrogen signaling in the development of prostate malignancy. Hence we hypothesize that TGFβ and other growth factors released from tumor cells can induce aromatase gene expression and activity in bone cells leading to an enhanced estradiol synthesis which would in turn lead to an increase in bone formation as estrogen is a known osteogenic factor. We examined the effect of TGFβ superfamily ligands on aromatase expression in pre-osteoblastic cells. Treatment with TGFβ1 and BMP-4/7 resulted in an increase in aromatase expression in both mouse pre-osteoblasts and human bone marrow-derived mesenchymal stem cells (MSC's). This increase in aromatase expression was abrogated after transient knockdown of Smad's in MSC's. Treatment with letrozole (aromatase inhibitor) as well as an anti-estrogen (ICI 182, 780) resulted in a decrease in osteoblastic differentiation of mesenchymal stem cells as measured by alkaline phosphatase activity assay and expression of osteogenic markers by quantitative real-time PCR analysis. Furthermore, PacMetUT1 cells were found to be responsive to 17-β estradiol treatment. 17-β estradiol treatment of PacMetUT1 cells resulted in an enhanced anchorage- dependent and independent cell growth in vitro. 17-β estradiol also induced a change in cell morphology of PacMetUT1 cells with a reduction in E-cadherin expression and an increase in Vimentin expression at both protein and mRNA level. This affect was abrogated after stable estrogen receptor alpha (ERα) knockdown in PacMetUT1 cells. Our results demonstrate an aromatase-mediated induction of osteogenesis by TGFβ superfamily ligands in the pre-osteoblastic cells and a stimulatory effect of estrogen signaling on PacMetUT1 cell tumorigencity in vitro. Future studies will delineate whether the induction of aromatase mediates osteoblastic bone metastasis of prostate cancer cells in vivo and if combination treatment of TGFβ and aromatase inhibitors can be used as a novel therapeutic strategy to alleviate bone metastasis in prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5317. doi:1538-7445.AM2012-5317
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