Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells.
The FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3025916?pdf=render |
| _version_ | 1828439007665586176 |
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| author | Fatouma Alimirah Xinjian Peng Genoveva Murillo Rajendra G Mehta |
| author_facet | Fatouma Alimirah Xinjian Peng Genoveva Murillo Rajendra G Mehta |
| author_sort | Fatouma Alimirah |
| collection | DOAJ |
| description | The FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at the second ATG site, resulting in a truncated protein with three less amino acids. Epidemiological studies have paradoxically implicated this polymorphism with increased breast cancer risk. 1α,25 (OH)(2)D(3), the active metabolite of vitamin D, is known to inhibit cell proliferation, induce apoptosis and potentiate differentiation in human breast cancer cells. It is well documented that 1α,25 (OH)(2)D(3) downregulates estrogen receptor α expression and inhibits estrogen mediated signaling in these cells. The functional significance of the VDR FokI polymorphism in vitamin D action is undefined.To elucidate the functional role of FokI polymorphism in breast cancer, MCF-7-Vector, MCF-7-VDRff and MCF-7-VDRFF stable cell lines were established from parental MCF-7 cells as single-cell clones. In response to 1α,25 (OH)(2)D(3) treatments, cell growth was inhibited by 60% in VDRFF cells compared to 28% in VDRff cells. The induction of the vitamin D target gene CYP24A1 mRNA was 1.8 fold higher in VDRFF cells than in VDRff cells. Estrogen receptor-α protein expression was downregulated by 62% in VDRFF cells compared to 25% in VDRff cells. VDR protein stability was greater in MCF-7-VDRFF cells in the presence of cycloheximide. PCR array analyses of VDRff and VDRFF cells revealed increased basal expression levels of pro-inflammatory genes Cyclooxygenase-2, Interleukin-8 and Chemokine (C-C Motif) Ligand 2 in MCF-7-VDRff cells by 14, 52.7 and 5 fold, respectively.These results suggest that a VDRff genotype may play a role in amplifying aggressive breast cancer, paving the way for understanding why some breast cancer cells respond inefficiently to vitamin D treatment. |
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| format | Article |
| id | doaj.art-088d8a0ebeb84417b239387324f48d7b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T20:17:07Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-088d8a0ebeb84417b239387324f48d7b2022-12-22T01:35:10ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0161e1602410.1371/journal.pone.0016024Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells.Fatouma AlimirahXinjian PengGenoveva MurilloRajendra G MehtaThe FokI vitamin D receptor (VDR) polymorphism results in different translation initiation sites on VDR. In the VDRff variant, initiation of translation occurs at the first ATG site, giving rise to a full length VDR protein of 427 amino acids. Conversely, in the VDRFF variant, translation begins at the second ATG site, resulting in a truncated protein with three less amino acids. Epidemiological studies have paradoxically implicated this polymorphism with increased breast cancer risk. 1α,25 (OH)(2)D(3), the active metabolite of vitamin D, is known to inhibit cell proliferation, induce apoptosis and potentiate differentiation in human breast cancer cells. It is well documented that 1α,25 (OH)(2)D(3) downregulates estrogen receptor α expression and inhibits estrogen mediated signaling in these cells. The functional significance of the VDR FokI polymorphism in vitamin D action is undefined.To elucidate the functional role of FokI polymorphism in breast cancer, MCF-7-Vector, MCF-7-VDRff and MCF-7-VDRFF stable cell lines were established from parental MCF-7 cells as single-cell clones. In response to 1α,25 (OH)(2)D(3) treatments, cell growth was inhibited by 60% in VDRFF cells compared to 28% in VDRff cells. The induction of the vitamin D target gene CYP24A1 mRNA was 1.8 fold higher in VDRFF cells than in VDRff cells. Estrogen receptor-α protein expression was downregulated by 62% in VDRFF cells compared to 25% in VDRff cells. VDR protein stability was greater in MCF-7-VDRFF cells in the presence of cycloheximide. PCR array analyses of VDRff and VDRFF cells revealed increased basal expression levels of pro-inflammatory genes Cyclooxygenase-2, Interleukin-8 and Chemokine (C-C Motif) Ligand 2 in MCF-7-VDRff cells by 14, 52.7 and 5 fold, respectively.These results suggest that a VDRff genotype may play a role in amplifying aggressive breast cancer, paving the way for understanding why some breast cancer cells respond inefficiently to vitamin D treatment.http://europepmc.org/articles/PMC3025916?pdf=render |
| spellingShingle | Fatouma Alimirah Xinjian Peng Genoveva Murillo Rajendra G Mehta Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. PLoS ONE |
| title | Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. |
| title_full | Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. |
| title_fullStr | Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. |
| title_full_unstemmed | Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. |
| title_short | Functional significance of vitamin D receptor FokI polymorphism in human breast cancer cells. |
| title_sort | functional significance of vitamin d receptor foki polymorphism in human breast cancer cells |
| url | http://europepmc.org/articles/PMC3025916?pdf=render |
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