Expression and role of Foxa proteins in prostate cancer

Abstract

The molecular mechanism(s) for prostate cancer progression to androgen independence are poorly understood. We have recently shown that Foxa1 and Foxa2 proteins are differentially expressed in epithelial cells during murine prostate development, growth, and adult function. Currently, the role of Foxa proteins in prostate cancer development and progression is unknown. Foxa protein expression was investigated in the LPB-Tag LADY mouse prostate cancer models, in human prostate cancer specimens, and various prostate cancer cell lines using Western blot and immunostaining analysis. In vitro transient transfection, studies were performed to investigate Foxa/prostate-specific gene regulation. Foxa1 was strongly expressed in areas of prostatic intraepithelial neoplasia (PIN) in both the androgen dependent 12T-7f and in the metastatic, androgen independent 12T-10 LADY models. Prominent Foxa1 and Foxa2 expression was observed in 12T-10 invasive undifferentiated neuroendocrine carcinomas, in the hormone independent and metastasizing 12T-10 derived, NE-10 allograft tumors, and in all metastatic lesions isolated from 12T-10 mice. Foxa1 protein expression was always observed in human prostate carcinomas, regardless of Gleason grade score, while Foxa2 was only detected in neuroendocrine small cell carcinomas and in some high Gleason score adenocarcinomas. Foxa proteins were also differentially expressed in three prostate cancer cell lines. Importantly, in vitro functional assays demonstrated that Foxa2 could activate androgen-dependent prostate-specific genes in an androgen receptor and ligand-independent manner. These results suggest that Foxa proteins are important in prostate carcinogenesis. In particular, Foxa2 may be involved in progression of prostate cancer to androgen independence. As such, Foxa proteins may represent novel targets for therapeutic intervention.

Neuroendocrine differentiation in the 12T‐10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells

“…3C), a marker of NE cells. In accordance with our previous report [14] the NE cells express Foxa2 (Fig. 3B).…”

BZL101, a phytochemical extract from theScutellaria barbataplant, disrupts proliferation of human breast and prostate cancer cells through distinct mechanisms dependent on the cancer cell phenotype

“…These transcription factors are through to have a roles in breast cancers cell proliferation and/or developmental processes. [21][22][23][24][25][26][27] Regardless of the nature of the precise BZL101-regulated transcription factor(s), our results suggest that within the BZL101 mixture, specific compounds act as selective estrogen receptor disruptors. We further observed that treatment of MCF7 cells strongly downregulated expression of both EGFR and the ErbB2/HER2 member of the EGF receptor gene family.…”

“…Within this BZL101 regulated region of the ERα promoter are consensus DNA binding sites for a number of transcription factors involved in developmental pathways and implicated in tumorigenesis, including HNF3-beta (FoxA2), 21,22 PRRX2, 23 GATA [24][25][26] and NKX-2.…”

Dissociation of Epithelial and Neuroendocrine Carcinoma Lineages in the Transgenic Adenocarcinoma of Mouse Prostate Model of Prostate Cancer

“…Foxa1 is expressed in the developing and mature mouse prostate whereas Foxa2 is present in prostatic buds early in development but disappears shortly after birth. 30,31 In the adult mouse prostate, Foxa2 is confined to sparse synaptophysin-positive neuroendocrine cells within periurethral prostatic ducts and is thought to be a marker of neuroendocrine differentiation. 31 In humans, FOXA1 is expressed in all prostate adenocarcinomas, regardless of Gleason grade, whereas FOXA2 is expressed only in high-grade prostatic carcinomas with neuroendocrine differentiation and in neuroendocrine small cell carcinomas of the prostate.…”