Abstract
T47D are unusual human breast cancer cells that do not require estrogen to synthesize high levels of progesterone receptors. These cells can, therefore, be used to study the mechanisms by which progesterone, freed of estrogen interference, controls the synthesis of its receptors. In a recent paper we described progesterone receptor translocation and a subsequent very rapid nuclear processing step that results in an apparent loss of 60 to 80% of cellular progesterone receptors, 30 to 60 min after progesterone treatment. This paper deals with the replenishment of cellular receptors following processing. If progesterone is removed from cells after 60 min of treatment, cytoplasmic progesterone receptors replenish in 16 to 20 h. However, replenishment occurs even during chronic progesterone treatment; this is an artifact created by the extremely rapid (t1/2 approximately 2 h) metabolism of progesterone in media exposed to cells. If progesterone metabolism is blocked, then replenishment is not seen, probably because the hormone continuously retranslocates the newly replenished sites. There is an early protein synthesis-dependent step; cycloheximide in the first 4 h inhibits replenishment 24 h later, but if cycloheximide is slightly delayed (beyond 4 h), replenishment proceeds normally. In contrast to progesterone, the synthetic progestin R5020 completely suppresses progesterone receptor replenishment even 96 h after its removal from the medium. This compound can bind covalently to receptors and may be very difficult to remove from cells. Clearly, progestin treatment, and by analogy, circulating progesterone, will have profound effects on cytoplasmic and nuclear progesterone receptor levels when these are measured in biopsied human tumors as an adjunct to endocrine therapy.
Highlights
T47D are unusual human breast cancercells that do regulatory factor is estradiol, since inall known estrogen/
In arecentstudy[15], we described the stoichiometric translocation of progesterone receptors
We show that replenishment is critically dependent on an early protein synthetic step; receptor recycling or progesterone receptor measurements are widely used to assess the hormone dependence of human breast and endometrial tumors, the factors that regulate the levels of thesereceptors are incompletely understood
Summary
In con- independent of exogenous estrogen controls [11,12].We have trast to progesterone, the synthetic progestin R5020 exploited these cells to study the effects of progesterone, freed completely suppresses progesterone receptor replenishment even 96 h after itsremoval from the medium. We show that replenishment is critically dependent on an early protein synthetic step; receptor recycling or progesterone receptor measurements are widely used to assess the hormone dependence of human breast and endometrial tumors, the factors that regulate the levels of thesereceptors are incompletely understood. We show that cytoplasmic receptor levels are acutely modulated by the presence of progesterone if its metabolism is prevented, andthatthe widely used synthetic progestin, R5020, has profound inhibitory effects on receptor replenishment This analog, which has high affinity for progesterone
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