Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer

Lee, Hong Jin; Líu, Hao; Goodman, Catherine; Ji, Yan; Maehr, Hubert; Uskoković, Milan R.; Notterman, Daniel A.; Reiß, Michael; Suh, Nanjoo

doi:10.1016/j.bcp.2006.04.030

Cited by 67 publications

(72 citation statements)

References 39 publications

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“…As shown in Fig. 2B, mRNA levels for BMP-2, BMP-6, and CYP24A1 were increased by Ro3582 at 12 h and more markedly at 24 h confirming our earlier studies (5,6), and these inductions were significantly inhibited by Go6976.…”

Section: Resultssupporting

confidence: 89%

“…We previously reported that Ro3582 activates Smad signaling and inhibits cell growth in MCF10AT1 cells (5,6). Here, we used the PKCa/PKChI inhibitor Go6976 to determine whether blocking Smad signaling by Go6976 would affect growth inhibition by Ro3582 in MCF10AT1 cells.…”

Section: Resultsmentioning

confidence: 98%

“…We recently reported that a novel Gemini vitamin D 3 analogue, Ro3582, strongly inhibited the growth of human MCF10AT1 breast epithelial cells (5,6). Mechanistic studies indicated that this compound activated BMP/Smad signaling, as determined by increased phosphorylation of Smad1/5, translocation of pSmad1/5 to the nucleus, and enhancement of the BMP/Smad transcriptional activity (6).…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that 1a,25(OH) 2 D 3 and a vitamin D 3 analogue Ro3582 activated the BMP signaling pathway, as shown by enhanced phosphorylation of the MH2 domain (Ser 463/465 ) of Smad1/5 in breast epithelial cells (5,6). We have now further explored the upstream kinase signaling pathways responsible for activation of BMP signaling by Ro3582 and for its role in growth inhibition of breast epithelial cells.…”

Section: Introductionmentioning

confidence: 97%

“…We previously reported that 1a,25(OH) 2 (Fig. 1), inhibited the proliferation of breast epithelial cells and activated the bone morphogenetic protein (BMP) signaling pathway (5,6).…”

Section: Introductionmentioning

confidence: 99%

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Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Lee

Paul

et al. 2007

Cancer Research

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Bone morphogenetic proteins (BMP) are members of the transforming growth factor-B superfamily, and they play an important role for embryonic development, for bone and cartilage formation, and during carcinogenesis. We have previously shown that the novel Gemini vitamin D 3 analogue, 1A,, inhibited cell proliferation and activated the BMP/Smad signaling pathway in MCF10AT1 breast epithelial cells. In this report, we investigated the upstream signaling pathways responsible for the activation of BMP/Smad signaling by Ro3582. Among seven different serine/threonine kinase inhibitors that we tested, protein kinase C (PKC) inhibitors blocked the effects of Ro3582 on the phosphorylation of Smad1/5, mRNA synthesis for BMP-2 and BMP-6, and cell growth in MCF10AT1 cells. Overexpression of PKCA, but not PKCE, PKCD or PKCZ isoforms, increased Ro3582-induced phosphorylation of Smad1/5, suggesting that PKCA mediates the activation of Smad signaling and inhibition of cell proliferation. Interestingly, the activation of Smad signaling by Ro3582 was shown in Ha-ras-transfected MCF10AT1 cells, but not in the parent cell line (MCF10A without Ras). Inhibiting Ras activity blocked the translocation of PKCA to the plasma membrane and the phosphorylation of Smad1/5 induced by Ro3582, indicating that Ras is necessary for the activation of PKCA and Smad signaling. In conclusion, Ro3582 inhibits cell proliferation and activates BMP/Smad signaling via a Ras and PKCA pathway in breast epithelial cells. [Cancer Res 2007;67(24):11840-7]

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

“…We previously reported that 1a,25(OH) 2 (Fig. 1), inhibited the proliferation of breast epithelial cells and activated the bone morphogenetic protein (BMP) signaling pathway (5,6).…”

Section: Introductionmentioning

confidence: 99%

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Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Lee

Paul

et al. 2007

Cancer Research

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Gene Signatures of 1,25‐Dihydroxyvitamin D₃ Exposure in Normal and Transformed Mammary Cells

Simmons

Beaudin

Narvaez

et al. 2015

J of Cellular Biochemistry

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To elucidate potential mediators of vitamin D receptor (VDR) action in breast cancer, we profiled the genomic effects of its ligand 1,25-dihydroxyvitamin D3 (1,25D) in cells derived from normal mammary tissue and breast cancer. In non-transformed hTERT-HME cells, 483 1,25D responsive entities in 42 pathways were identified, whereas in MCF7 breast cancer cells, 249 1,25D responsive entities in 31 pathways were identified. Only 21 annotated genes were commonly altered by 1,25D in both MCF7 and hTERT-HME cells. Gene set enrichment analysis highlighted eight pathways (including senescence/autophagy, TGFβ signaling, endochondral ossification, and adipogenesis) commonly altered by 1,25D in hTERT-HME and MCF7 cells. Regulation of a subset of immune (CD14, IL1RL1, MALL, CAMP, SEMA6D, TREM1, CSF1, IL33, TLR4) and metabolic (ITGB3, SLC1A1, G6PD, GLUL, HIF1A, KDR, BIRC3) genes by 1,25D was confirmed in hTERT-HME cells and similar changes were observed in another comparable non-transformed mammary cell line (HME cells). The effects of 1,25D on these genes were retained in HME cells expressing SV40 large T antigen but were selectively abrogated in HME cells expressing SV40 + RAS and in MCF7 cells. Integration of the datasets from hTERT-HME and MCF7 cells with publically available RNA-SEQ data from 1,25D treated SKBR3 breast cancer cells enabled identification of an 11-gene signature representative of 1,25D exposure in all three breast-derived cell lines. Four of these 11 genes (CYP24A1, CLMN, EFTUD1, and SERPINB1) were also identified as 1,25D responsive in human breast tumor explants, suggesting that this gene signature may prove useful as a biomarker of vitamin D exposure in breast tissue.

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Endogenous bone morphogenetic proteins mediate 1α, 25‐dihydroxyvitamin D₃‐induced expression of osteoblast differentiation markers in human dermal fibroblasts

Hee

Nicoll

2008

Journal Orthopaedic Research

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Human dermal fibroblasts are generally considered to be restricted to a fibroblastic lineage. Although dermal fibroblasts do not typically express markers of osteoblastic differentiation, they have previously been shown to undergo osteoinduction when stimulated with bone morphogenetic proteins (BMPs) or vitamin D 3 . However, involvement of BMP signaling in vitamin D 3 -mediated osteoinduction has not been reported. In this study, human dermal fibroblasts were cultured in chemically defined medium containing vitamin D 3 , in the presence of the BMP antagonist noggin or neutralizing antibodies specific for BMP-4 or BMP-6, and characterized for markers of osteoblastic differentiation. Treatment of dermal fibroblasts with vitamin D 3 induced expression of BMP-4 (1.2 AE 0.2, 1.7 AE 0.2, and 1.8 AE 0.2 relative fold increase) and BMP-6 (9.1 AE 0.3, 23.3 AE 2.1, and 30.4 AE 3.0 relative fold increase) at 3, 14, and 21 days, respectively. Vitamin D 3 was also shown to induce the expression of the osteoblast-specific markers, alkaline phosphatase and osteocalcin, in a dose-dependent manner in human dermal fibroblasts. Addition of noggin, BMP-4 antibodies, and BMP-6 antibodies resulted in a downregulation of alkaline phosphatase activity (by 42%, 22%, and 20%, respectively) and secreted osteocalcin (by 20%, 31%, and 49%, respectively) after 21 days in culture. However, blocking BMP signaling did not result in complete recovery of a fibroblastic phenotype. Taken together, these results suggest that BMP signaling plays a role in the induction of an osteoblastic phenotype in human dermal fibroblasts in response to vitamin D 3 stimulation. Individually, vitamin D 3 and BMPs are known to enhance osteoblastic differentiation in stromal cells and osteoblasts. Vitamin D 3 acts primarily through nuclear receptors that bind vitamin D response elements in the promoters of osteoblast-specific genes, such as alkaline phosphatase and osteocalcin. 8,9 Vitamin D 3 is known to enhance differentiation and maturation of osteoblasts, although it has also been used for the osteoblastic differentiation of other cell types, including fibroblasts 6,7 and stromal cells. 10,11 BMP family members, including BMP-2, -4, and -6, act as potent stimulators of osteoblast differentiation, mainly signaling through cell surface receptors and the intracellular SMAD pathway to effect changes in gene expression. 12,13 Interactions between the vitamin D 3 and BMP pathways have also been observed. For example, expression of BMP-2, -3, -4, -5, and -6, have been shown to be regulated by vitamin D 3 or its analogs in a variety of cell types, including osteosarcoma, bone marrow stromal, squamous carcinoma, and breast and prostatic epithelial cells. [14][15][16][17][18][19][20] The mechanism by which vitamin D 3 induces BMP expression is not known, though potential vitamin D response elements have been identified bioinformatically. 21 Still, the effects of vitamin D 3 on BMP signaling and the expression of osteoblast-specific proteins in dermal fibroblasts...

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Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer

Cited by 67 publications

References 39 publications

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Gene Signatures of 1,25‐Dihydroxyvitamin D₃ Exposure in Normal and Transformed Mammary Cells

Endogenous bone morphogenetic proteins mediate 1α, 25‐dihydroxyvitamin D₃‐induced expression of osteoblast differentiation markers in human dermal fibroblasts

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Gene expression profiling changes induced by a novel Gemini Vitamin D derivative during the progression of breast cancer

Cited by 67 publications

References 39 publications

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Activation of Bone Morphogenetic Protein Signaling by a Gemini Vitamin D3 Analogue Is Mediated by Ras/Protein Kinase Cα

Gene Signatures of 1,25‐Dihydroxyvitamin D3 Exposure in Normal and Transformed Mammary Cells

Endogenous bone morphogenetic proteins mediate 1α, 25‐dihydroxyvitamin D3‐induced expression of osteoblast differentiation markers in human dermal fibroblasts

Contact Info

Product

Resources

About

Gene Signatures of 1,25‐Dihydroxyvitamin D₃ Exposure in Normal and Transformed Mammary Cells

Endogenous bone morphogenetic proteins mediate 1α, 25‐dihydroxyvitamin D₃‐induced expression of osteoblast differentiation markers in human dermal fibroblasts