Progestins and androgens stimulate lipid accumulation in T47D breast cancer cells via their own receptors

Chambon, Monique; Rochefort, Henri; Vial, Henri; Chalbos, Dany

doi:10.1016/0022-4731(89)90240-9

Cited by 33 publications

(21 citation statements)

References 16 publications

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“…Both ORG 2058 and the androgen/ progestin R1881 induced significant accumulation of both lipid and FAS mRNA in the control cells (Figures 7d and e). Androgens have been reported to induce lipogenesis in T-47D cells, albeit not to the same extent as progestins (Chambon et al, 1989), and accordingly we only observed modest effects of DHT on lipid production or FAS mRNA in the vector control cells. ICI 182780 and OH-Tam also either induced marginal lipid and FAS mRNA accumulation or had no effect (Figures 7d and e).…”

Section: Wt1 and Progestin Effects In Breast Cancer Cellssupporting

confidence: 44%

“…Progestins increase lipid biosynthesis in T-47D cells (Chambon et al, 1989), and Wt1 overexpression downregulates lipid metabolism pathways in HEK293 cells (Rae et al, 2004). We investigated whether the downregulation of Wt1 by siRNA would induce the accumulation of lipid, using Oil-Red-O, a stain specific to lipids found in intracytoplasmic fat droplets (Ramı´r-ez-Zacarı´as et al, 1992).…”

Section: Sirna-mediated Decrease In Wt1 Expression Increases Lipogenementioning

confidence: 99%

“…However, T-47D cells treated with Wt1 siRNA for 4 days showed a modest, but statistically significant, increase in levels of fatty acid synthetase (FAS) mRNA (Po0.02; Figure 4b). FAS is an important enzyme in lipogenesis and an indicator of activation of the lipid synthesis pathway in these cells (Horton et al, 2002), as well as being a known target of progestins (Chambon et al, 1989). We identified siRNA Protein levels were quantitated by densitometry.…”

Section: Sirna-mediated Decrease In Wt1 Expression Increases Lipogenementioning

confidence: 99%

“…Progestins have a biphasic effect on the proliferation of breast cancer cells in culture, initially stimulating G 1 cells to enter S phase, but the predominant effect is longterm growth inhibition and differentiation (Musgrove et al, 1991;Kester et al, 1997;Sutherland et al, 1998), including lipogenesis (Chambon et al, 1989). Progestin treatment inhibits cell cycle progression by decreasing cyclin D1 and cyclin E and the activity of their associated cyclin-dependent kinases (CDKs) (Musgrove et al, , 2001, decreasing c-Myc and modulating CDK complex formation through increases in the CDK inhibitors p18 INK4C , p21…”

Section: Introductionmentioning

confidence: 99%

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Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation

et al. 2007

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Progesterone regulates the proliferation and differentiation of normal mammary epithelium. In breast cancer cells, progesterone and its synthetic analogs, progestins, induce long-term growth inhibition and differentiation. However, the mechanisms responsible are not fully understood. When T-47D breast cancer cells were treated with the synthetic progestin ORG 2058 (16a-ethoxy-21-hydroxy-19-norpregn-4-en-3,20-dione), all isoforms of Wilms' tumor protein 1 (Wt1) mRNA and protein were rapidly downregulated. We reasoned that the decrease in Wt1 levels may contribute to the long-term antiproliferative and differentiative effects of progestins as proliferation and differentiation are known end points of Wt1 action. Consistent with this idea, Wt1 small interfering RNA led to a decrease in S phase and cyclin D1 levels, and increased Oil-Red-O staining, indicating increased lipogenesis. Conversely, overexpression of Wt1 attenuated the decrease in S phase induced by ORG 2058 at 48-96 h. This was accompanied by the sustained expression of cyclin D1 despite progestin treatment, and increased levels of retinoblastoma (Rb) phosphorylation at sites targeted by cyclin D1-Cdk4 (Ser249/Thr252). Wt1 overexpression also attenuated the ORG 2058-mediated increase in fatty acid synthase levels and reduced lipogenesis. Thus, Wt1 downregulation was sufficient to mimic the effects of progestin and was necessary for complete progestinmediated proliferative arrest and subsequent differentiation. Furthermore, Wt1 overexpression modulated the effects of progestins but not anti-estrogens or androgens. These results indicate that Wt1 is an important early target of progestins that regulates both proliferation and differentiation in breast cancer cells.

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Section: Wt1 and Progestin Effects In Breast Cancer Cellssupporting

confidence: 44%

Section: Sirna-mediated Decrease In Wt1 Expression Increases Lipogenementioning

confidence: 99%

Section: Sirna-mediated Decrease In Wt1 Expression Increases Lipogenementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation

et al. 2007

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“…In human cancer cell lines (MCF7, T47 D) cultured on plastic, progestins inhibit rather than stimulate cell division. This could be due to their anti-estrogenic activity [45] and/or to triglycerides accumulation in lipid droplets observed in T47 D cells [46]. However, in normal human mammary glands growing within a Matrigel matrix [47], progesterone appears to be mitogenic, and lipid droplets generally do not accumulate in vivo in breast or prostate cancer [36].…”

Section: Prs In Breast Cancermentioning

confidence: 99%

The Role of Sex Steroid Receptors on Lipogenesis in Breast and Prostate Carcinogenesis: A Viewpoint

Rochefort

Chalbos

2010

HORM CANC

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Cancer cells require both nutrients and mitogens to multiply and survive in the unfavorable microenvironment of solid tumors or metastases before angiogenesis. Most cancer cells do not use fatty acids (FA) from the circulation but synthesize them in situ especially to make membranes and lipid signals required for continuously dividing cells. Three lipogenic enzymes are overexpressed, induced by sex steroid hormones and responsible for the in situ increased lipogenesis in cancer cells. We propose that in the early stages of human breast and prostate carcinogenesis, an increased activity of sex steroid receptors is partly responsible for the overexpression of FA synthase (FASN) whose regulation in cancer cells has been particularly studied. Increased activity of androgen receptor (AR), via different mechanisms, was extensively reported in prostate cancer. An increased level/and or activity of progesterone receptors, correlated with an increased expression of FASN, was found both in early stages of breast carcinogenesis and during the hormone replacement therapy of menopausal women. While the majority of recent targeted therapies are based on inhibition of mitogenic pathways, the inhibition of cancer cell nutrition by interfering with lipid synthesis and hormone action should open the way to new therapeutic and preventive approaches of hormonedependent cancers.

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Progestins and Androgens Increase Expression of Spot 14 in T47-D Breast Tumor Cells

Heemers

Vanderhoydonc

Heyns

et al. 2000

Biochemical and Biophysical Research Communications

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Progestins and androgens stimulate lipid accumulation in T47D breast cancer cells via their own receptors

Cited by 33 publications

References 16 publications

Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation

Wilms' tumor protein 1: an early target of progestin regulation in T-47D breast cancer cells that modulates proliferation and differentiation

The Role of Sex Steroid Receptors on Lipogenesis in Breast and Prostate Carcinogenesis: A Viewpoint

Progestins and Androgens Increase Expression of Spot 14 in T47-D Breast Tumor Cells

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