The phosphatase and tensin homolog （PTEN） and the zinc finger homeobox 3 （ZFHX3）/AT-motif binding factor 1 （ATBF1） genes have been established as tumor suppressor genes in prostate cancer by their frequent delet...The phosphatase and tensin homolog （PTEN） and the zinc finger homeobox 3 （ZFHX3）/AT-motif binding factor 1 （ATBF1） genes have been established as tumor suppressor genes in prostate cancer by their frequent deletions and mutations in human prostate cancer and by the formation of mouse prostatic intraepithelial neoplasia （mPIN） or tumor by their deletions in mouse prostates. However, whether ZFHX3/ATBF1 deletion together with PTEN deletion facilitates prostatic tumorigenesis is unknown. In this study, we simultaneously deleted both genes in mouse prostatic epithelia and performed histological and molecular analyses. While deletion of one Pten allele alone caused low-grade （LG） mPIN as previously reported, concurrent deletion of Zfhx3/Atbfl promoted the progression to high-grade （HG） mPIN or early carcinoma. ZJhx3/Atbfl and Pten deletions together increased cell proliferation, disrupted the smooth muscle layer between epithelium and stroma, and increased the number of apoptotic cells. Deletion of both genes also accelerated the activation of Akt and Erkl/2 oncoproteins. These results suggest an additive effect of ZFHX3/ATBF1 and PTEN deletions on the development and progression of prostate neoplasia.展开更多
Progesterone(Pg)/progesterone receptor(PR) signaling drives mammary gland side-branching and alveologenesis, but the mechanisms through which Pg/PR signaling functions remain to be clarified.Using in vitro and in vivo...Progesterone(Pg)/progesterone receptor(PR) signaling drives mammary gland side-branching and alveologenesis, but the mechanisms through which Pg/PR signaling functions remain to be clarified.Using in vitro and in vivo models and histological and molecular analyses, we determined the role of Zfhx3 transcription factor in mammary gland development driven by Pg/PR signaling. Postnatal deletion of Zfhx3 in mouse mammary epithelial cells attenuated side-branching morphogenesis and alveologenesis. These effects were undetectable in the absence of Pg/PR signaling. During the estrus cycle, Zfhx3 expression corresponded to that of Pg, being at the highest level at the diestrus stage; Zfhx3 deletion inhibited mammary gland branching more potently at diestrus than estrus stage. Loss of Zfhx3 not only attenuated the expansion of stem/progenitor cells driven by Pg/PR signaling, but also impaired the function of Pg/PR signaling in the transcriptional activation of multiple genes. In addition, Pg/PR signaling significantly expanded PR-and Zfhx3-positive epithelial cells, and induced the physical association of ZFHX3 with PR. These findings establish Zfhx3 as an integral transcription factor of Pg/PR signaling in driving side-branching and alveologenesis during mammary gland development.展开更多
基金supported in part by the grants from the National Cancer Institute(NCI)(No.R01CA121459)the National Institutes of Health(NIH)+1 种基金supported in part by the Integrated Cellular Imaging Shared Resource of Winship Cancer Institute of Emory Universitythe NIH/NCI under award number P30CA138292
文摘The phosphatase and tensin homolog （PTEN） and the zinc finger homeobox 3 （ZFHX3）/AT-motif binding factor 1 （ATBF1） genes have been established as tumor suppressor genes in prostate cancer by their frequent deletions and mutations in human prostate cancer and by the formation of mouse prostatic intraepithelial neoplasia （mPIN） or tumor by their deletions in mouse prostates. However, whether ZFHX3/ATBF1 deletion together with PTEN deletion facilitates prostatic tumorigenesis is unknown. In this study, we simultaneously deleted both genes in mouse prostatic epithelia and performed histological and molecular analyses. While deletion of one Pten allele alone caused low-grade （LG） mPIN as previously reported, concurrent deletion of Zfhx3/Atbfl promoted the progression to high-grade （HG） mPIN or early carcinoma. ZJhx3/Atbfl and Pten deletions together increased cell proliferation, disrupted the smooth muscle layer between epithelium and stroma, and increased the number of apoptotic cells. Deletion of both genes also accelerated the activation of Akt and Erkl/2 oncoproteins. These results suggest an additive effect of ZFHX3/ATBF1 and PTEN deletions on the development and progression of prostate neoplasia.
基金supported by grant No. 81472464 from the National Natural Science Foundation of China
文摘Progesterone(Pg)/progesterone receptor(PR) signaling drives mammary gland side-branching and alveologenesis, but the mechanisms through which Pg/PR signaling functions remain to be clarified.Using in vitro and in vivo models and histological and molecular analyses, we determined the role of Zfhx3 transcription factor in mammary gland development driven by Pg/PR signaling. Postnatal deletion of Zfhx3 in mouse mammary epithelial cells attenuated side-branching morphogenesis and alveologenesis. These effects were undetectable in the absence of Pg/PR signaling. During the estrus cycle, Zfhx3 expression corresponded to that of Pg, being at the highest level at the diestrus stage; Zfhx3 deletion inhibited mammary gland branching more potently at diestrus than estrus stage. Loss of Zfhx3 not only attenuated the expansion of stem/progenitor cells driven by Pg/PR signaling, but also impaired the function of Pg/PR signaling in the transcriptional activation of multiple genes. In addition, Pg/PR signaling significantly expanded PR-and Zfhx3-positive epithelial cells, and induced the physical association of ZFHX3 with PR. These findings establish Zfhx3 as an integral transcription factor of Pg/PR signaling in driving side-branching and alveologenesis during mammary gland development.
