The structure and function of progesterone receptors in breast cancer

Horwitz, Kathryn B.

doi:10.1016/0022-4731(87)90339-6

Cited by 30 publications

(17 citation statements)

References 79 publications

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“…H o w e v e r , the overwhelming clinical evidence for tumor regression observed in 20 to 50% of pre-and post-menopausal breast cancer patients treated with various androgens [7] favors the view that naturally occuring androgens might constitute an as yet overlooked, direct hormonal control of m a m m a r y cancer cell growth. It is thus reasonable to suggest that an imbalance between androgenic and estrogenic influences could modify the overall growth rate of breast tumors in much the same way as that suggested for progestins in estrogen target tissues [60]. Interestingly, the indication that an increased response rate might be obtained by combining androgens and an antiestrogen therapy in breast cancer patients [5] is in agreement with our observation that the mechanisms of inhibition by both types of agents are different, and their effects, at least in part, additive.…”

Section: Discussionmentioning

confidence: 94%

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Poulin

Baker

Labrie

1988

Breast Cancer Res Tr

159

103

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This study describes the inhibitory effect of 5 alpha-dihydrotestosterone (5 alpha-DHT) and its precursors testosterone (T) and androst-4-ene-3,17-dione (delta 4-DIONE) on the growth of the estrogen-sensitive human breast cancer cell line ZR-75-1. In the absence of estrogens, cell proliferation measured after a 12-day incubation period was 50-60% inhibited by maximal concentrations of 5 alpha-DHT, T, or delta 4-DIONE with half-maximal effects (IC50 values) observed at 0.10, 0.15 and 15 nM, respectively. This growth inhibition by androgens was due to an increase in generation time and a lowering of the saturation density of cell cultures. The antiestrogen LY156758 (300 nM) induced 25-30% inhibition of basal cell growth, its effect being additive to that of 5 alpha-DHT. The mitogenic effect of 1 nM estradiol (E2) was completely inhibited by increasing concentrations of 5 alpha-DHT with a potency (IC50 = 0.10 nM) similar to that measured when the androgen was used alone. E2 had a more rapid effect on cell proliferation than 5 alpha-DHT, the latter requiring at least 5 to 6 days to exert significant growth inhibition. As found in the absence of estrogens, maximal inhibition of cell proliferation in the presence of E2 was achieved by the combination of the antiestrogen and 5 alpha-DHT. Supraphysiological concentrations of E2 (up to 1 microM) were needed to completely reverse the growth inhibitory effect of a submaximal concentration of 5 alpha-DHT (1 nM). The antiproliferative effect of androgens was competitively reversed by the antiandrogen hydroxyflutamide, thus indicating an androgen receptor-mediated mechanism. The present data suggest the potential benefits of an androgen-antiestrogen combination therapy in the endocrine management of breast cancer.

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Section: Discussionmentioning

confidence: 94%

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Poulin

Baker

Labrie

1988

Breast Cancer Res Tr

159

103

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“…The widely held notion that MPA favors tumor regression mainly through its progestin-like activity [1,2,4,5,14,21,22] should be reevaluated in view of its potential androgenic and glucocorticoid activities at the tumor level. The high correlation of response to progestin therapy with ER/PgR positivity [1,2,4,5] cannot be taken as evidence for a PgR-based mechanism of action of MPA, since it is also common to most other types of endocrine manipulations [6,23,54].…”

Section: Discussionmentioning

confidence: 99%

“…The overall response rate to this progestin averages 40% in unselected breast cancer patients [5], an efficacy comparable to that of the non-steroidal antiestrogen tamoxifen [6]. Its more general use, however, is for breast cancer relapsing after other endocrine therapeutic modalities.…”

Section: Introductionmentioning

confidence: 99%

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Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells

Poulin

Baker

Poirier

et al. 1989

Breast Cancer Res Tr

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Medroxyprogesterone acetate (MPA) is a synthetic progestin, currently used in the adjuvant treatment of advanced breast cancer, which induces remission rates (30-40%) comparable to those obtained with other types of endocrine therapies. Since, in addition to its progestin-like action, MPA exhibits androgen- and glucocorticoid-like activities in other tissues, the present study was designed to assess the relative contribution of the different steroid receptor systems in the direct action of MPA on breast cancer cell growth, using the ZR-75-1 human mammary carcinoma cell line as an in vitro model. Unlike pure progestins, MPA potently inhibited the proliferation of ZR-75-1 cells in a concentration-dependent manner either in the presence or in the absence of estrogens, and the addition of insulin had only marginal effects on its growth-inhibitory activity. On the other hand, both hydroxyflutamide (OHF, a non-steroidal monospecific antiandrogen) and RU486 (a potent antiglucocorticoid and antiprogestin also endowed with antiandrogenic activity) competitively reversed MPA antiproliferative effects. MPA further decreased the growth of ZR-75-1 cells co-incubated with maximally inhibitory concentrations of either 5 alpha-dihydrotestosterone (DHT) or dexamethasone (DEX), although at about 300-fold higher MPA concentrations with DHT-treated than with DEX-treated ZR-75-1 cells, thus demonstrating a highly predominant androgenic effect. However, MPA had no effect on the growth of ZR-75-1 cells co-incubated with DHT and DEX simultaneously, thus supporting the predominant role of androgen and glucocorticoid receptors in MPA action. A 12-day preincubation of ZR-75-1 cells with increasing concentrations of MPA (10(-12) to 3 x 10(-6)M) decreased the specific uptake of [3H]estradiol (E2) by intact cell monolayers to the same extent as 10 nM DHT, an effect which was competitively blocked by the addition of OHF (3 microM). MPA action on ZR-75-1 cell growth also significantly differed from that of progestins in being additive to the inhibition of E2-stimulated growth by the steroidal antiestrogen ICI164384. The present data indicate that the main action of MPA on ZR-75-1 human breast cancer cell growth is due to its androgen receptor-mediated inhibitory action, while its glucocorticoid-like activity could play an additional role at high concentrations.

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“…However, a PR-based radioligand has some potential advantages over an ER-based one: (1) there is a better correlation between PR status and hormonal responsiveness than there is with ER status [25][26][27][28][29]; (2) a PR-based ligand could be used after the initiation of anti-estrogen hormonal therapy, whereas an ERbased one would not be useful when tumor ER is saturated by the hormonal agent [30]. Moreover, (3) PR-based ligands may benefit from the increased PR levels induced by the transient agonistic effect of tamoxifen during the initial course of tamoxifen treatment of breast tumor [31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

Sharp

Fettig

Lee

et al. 2008

Nuclear Medicine and Biology

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Introduction-Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy. Results-[ 76 Br]3 was synthesized in 5% overall yield with specific activity being 200~1250 Ci/ mmol. [ 76 Br]3 demonstrated high PR-mediated uptake in the target tissue uterus (8.72 ± 1.84 %ID/ g at 1 h) that was reduced by a blocking dose of unlabeled progestin R5020, but the non-specific uptake in blood and muscle (2.11 ± 0.14 and 0.89 ± 0.16 %ID/g at 1 h, respectively) was relatively high. [ 76 Br]3 was stable in whole rat blood in vitro, but it was not stable in vivo due to the fast metabolism that occurred in the liver, resulting in the formation of a more polar radioactive metabolite and free [ 76 Br]bromide. The level of free [ 76 Br]bromide in blood remained high during the experiment (2.11 ± 0.14 %ID/g at 1 h and 1.52 ± 0.24 %ID/g at 24 h). The tissue distribution of [ 76 Br]3 at 1 and 3 hours was compared with that of the 18 F analogs, [ 18 F]FFNP 1 and ketal 2. Method-16α,17α-[(R)-1'-α-(5-[ Conclusion-[76 Br]3 may have potential for imaging PR positive breast tumors at early time points, but it is not suitable for imaging at later times or for radiotherapy.

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The structure and function of progesterone receptors in breast cancer

Cited by 30 publications

References 79 publications

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells

Evaluation of a bromine-76-labeled progestin 16α,17α-dioxolane for breast tumor imaging and radiotherapy: in vivo biodistribution and metabolic stability studies

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