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Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells

Oncogene volume 21, pages 761–768 (2002)Cite this article

Abstract

T47D cells represent an estrogen-responsive human ductal carcinoma cell line which expresses detectable levels of estrogen receptor (ER). We have previously shown that estradiol (E2) treatment of T47D cells causes an increase in the level of p53 and a concomitant phosphorylation of retinoblastoma protein (pRb). In the present study, we have analysed the expression of p53 and phosphorylation state of pRb and compared the effects of E2 and triiodothyronine (T3) on these phenomena. Cells were grown in a medium containing charcoal-treated serum to deplete the levels of endogenous steroids. Upon confluency, the cells were treated with T3 (10−12 to 10−7 M) for 24 h and the presence of p53 and pRb was detected by Western analysis. E2 treatment of cells caused a 2–3-fold increase in the level of p53. Presence of T3 in the medium caused a gradual increase in the level of p53 in a concentration-dependent manner. Under the above conditions, pRb was phosphorylated (detected as an upshift during SDS–PAGE) in the presence of E2 and T3. Supplementation of growth medium with T3 (1 μM) caused an increase in the rate of proliferation of T47D cells and induced hyperphosphorylation of pRb within 4 h; this effect was maintained for up to 12 h. When ICI 164 384 (ICI) (1 μM), an ER antagonist, was combined with E2 (1 nM) or T3 (1 μM), effects of hormones on cell proliferation and hyperphosphorylation of pRb were blocked. Western analysis of p53 was supplemented with its cytolocalization by immuno-labeling using laser scanning confocal fluorescence microscopy, which revealed an ICI-sensitive increase in the abundance of p53 in hormone-treated cells. Steroid binding analysis revealed lack of competition by T3 for the [3H]E2 binding. These results indicate that T3 regulates T47D cell cycle progression and proliferation raising the p53 level and causing hyperphosphorylation of pRb by a common mechanism involving ER and T3 receptor (T3R)-mediated pathways.

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Abbreviations

ATCC:

American type culture collection

E2:

17-β estradiol

ECL:

enhanced chemiluminescence

ERE:

estrogen response element

FBS:

fetal bovine serum

ER:

estrogen receptor

HBSS:

Hanks' balanced salt solution

HSS:

high speed supernatant

ICI:

ICI 164 384

OHT:

4-hydroxy tamoxifen

p53:

53-kDa tumor suppressor protein

PBS:

phosphate-buffered saline

PMSF:

phenylmethylsulfonyl fluoride

PVDF:

polyvinylidene fluoride

PR:

progesterone receptor

pRb:

retinoblastoma protein

ppRb:

phosphorylated pRb

Rb:

retinoblastoma

SDS–PAGE:

sodium dodecyl sulfate polyacrylamide gel electrophoresis

SSFBS:

single stripped fetal bovine serum

T3:

triiodothyronine

TAM:

tamoxifen

T3R:

thyroid hormone receptor

TRE:

thyroid hormone response element.

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Acknowledgements

The studies were supported in part by National Institutes of Health, and the Research Excellence Fund, Center for Biomedical Research, Oakland University.

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  1. Department of Biological Sciences and Center for Biomedical Research, Oakland University, Rochester, 48309, Michigan, MI, USA

    Sumi Dinda, Amelita Sanchez & Virinder Moudgil

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  1. Sumi Dinda
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Correspondence to Virinder Moudgil.

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Dinda, S., Sanchez, A. & Moudgil, V. Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Oncogene 21, 761–768 (2002). https://doi.org/10.1038/sj.onc.1205136

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