Loss of SPDEF and gain of TGFBI activity after androgen deprivation therapy promote EMT and bone metastasis of prostate cancer

Loss of a TGFβ signaling repressor by androgen deprivation therapy shows how a common treatment for primary prostate cancer may promote metastasis. Metastatic effects of primary prostate cancer therapy Metastatic progression in patients with prostate cancer is common despite pharmacological inhibition of androgen receptor signaling. This drug resistance is associated with increased signaling through the transforming growth factor–β (TGFβ) signaling pathway, and Chen et al. have identified why. In both cultured prostate tumor cells and in tumor-bearing mouse models, the authors found that activation of the androgen receptor induces a transcriptional repressor (called SPDEF) of TGFβ-induced protein (TGFBI), which mediates cell adhesion to the extracellular matrix, a behavior that can facilitate metastasis. However, androgen deprivation therapy (ADT), a common clinical strategy, decreases the abundance of SPDEF and consequently increases that of TGFBI, thereby promoting the metastasis of prostate tumor cells. These findings are another example of how therapies that prevent growth in the primary tumor can inadvertently promote metastasis. Androgen deprivation therapy (ADT) targeting the androgen receptor (AR) is a standard therapeutic regimen for treating prostate cancer. However, most tumors progress to metastatic castration-resistant prostate cancer after ADT. We identified the type 1, 2, and 4 collagen–binding protein transforming growth factor–β (TGFβ)–induced protein (TGFBI) as an important factor in the epithelial-to-mesenchymal transition (EMT) and malignant progression of prostate cancer. In prostate cancer cell lines, AR signaling stimulated the activity of the transcription factor SPDEF, which repressed the expression of TGFBI. ADT, AR antagonism, or overexpression of TGFBI inhibited the activity of SPDEF and enhanced the proliferation rates of prostate cancer cells. Knockdown of TGFBI suppressed migration and proliferation in cultured cells and reduced prostate tumor growth and brain and bone metastasis in xenograft models, extending the survival of tumor-bearing mice. Analysis of prostate tissue samples collected before and after ADT from the same patients showed that ADT reduced the nuclear abundance of SPDEF and increased the production of TGFBI. Our findings suggest that induction of TGFBI promotes prostate cancer growth and metastasis and can be caused by dysregulation or therapeutic inhibition of AR signaling.