Differential regulation of retinoblastoma protein by hormonal and antihormonal agents in T47D breast cancer cells.

Abstract

Phosphorylation of the tumor suppressor protein, retinoblastoma (pRb), regulates the progression of the cell cycle. Previous work from this laboratory had shown that estradiol (E(2)) regulates tumor suppressor proteins, p53 and retinoblastoma in breast cancer cells. In the present study, we have examined the phosphorylation of pRB in T47D breast cancer cells following treatments with R5020 and antiprogestins. In growth medium containing serum depleted of endogenous steroids by charcoal treatment, pRb appeared mainly in its hypophosphorylated form. Addition of 10 nM R5020 to the culture medium caused hyperphosphorylation of pRb within 24 h, but the hypophosphorylated form of pRb began to accumulate after 72 h. Upon prolonged R5020 treatment (72-96 h), pRb was detected exclusively in its hypophosphorylated form. While treatment of cells with R5020 caused a transient increase in the level of cyclin D1, E(2) addition caused a sustained increase in the level of cyclin D1 consistent with its role in stimulating pRb phosphorylation. Antagonists of both estrogen receptor (ER) and progesterone receptor (PR) blocked the E(2) and R5020-induced pRb phosphorylation, respectively. These results suggest that R5020 induces pRb phosphorylation via a transient increased expression of cyclin D1, whereas E(2) treatment results in sustained expression of cyclin D1 and increased pRb phosphorylation. Furthermore, R5020 effects on pRb phosphorylation appear PR-mediated as no cross-antagonism of pRb phosphorylation was observed: the R5020 effects were blocked by RU486 and ZK98299, but not by the pure ER antagonist, ICI 182, 780 (ICI).

• Authors: P Alban, C Hurd, S Dinda, N Khattree, V K Moudgil
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 77 Issue 2-3 Pg. 135-41 (May 2001) ISSN: 0960-0760 [Print] England
• PMID: 11377979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Estrogen Receptor Modulators
• Estrogens
• Gonanes
• Receptors, Estrogen
• Receptors, Progesterone
• Retinoblastoma Protein
• Fulvestrant
• Mifepristone
• Progesterone
• Estradiol
• Promegestone
• onapristone

Topics

• Breast Neoplasms (metabolism, pathology)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor Modulators (pharmacology)
• Estrogens (pharmacology)
• Fulvestrant
• Gonanes (pharmacology)
• Humans
• Mifepristone (pharmacology)
• Phosphorylation
• Progesterone (antagonists & inhibitors, pharmacology)
• Promegestone (pharmacology)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Retinoblastoma Protein (metabolism)
• Tumor Cells, Cultured