Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer

Klijn, Jan G.M.; Setyono-Han, Buddy; Foekens, John A.

doi:10.1016/s0039-128x(00)00195-1

Cited by 140 publications

(98 citation statements)

References 27 publications

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“…In breast cancer patients, positive responses with RU486 have been reported (Klijn et al 1989). In this series, most side effects were related to the antiglucocorticoid activity of RU486, thus illustrating the need of pure Endocrine-Related Cancer (2009) 16 333-350 www.endocrinology-journals.org antiprogestins (Klijn et al 2000). Both RU486 and ZK 98299 were also shown to inhibit DMBA and MNUinduced mammary carcinomas in rats, as well as the MXT mouse tumors (Michna et al 1989a,b, Schneider et al 1989.…”

Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 75%

“…It is possible, as NK have been shown to be modulated by progestins (Arruvito et al 2008), that an immune-mediated mechanism may contribute to their efficacy (Check et al 2007). Several groups have reported that the combination of antiprogestins and antiestrogens in breast cancer treatment was more efficacious than single drug treatments (Klijn et al 2000). Experimentally, in MCF-7 cells transplanted in estrogen-treated nude mice, the simultaneous administration of tamoxifen and antiprogestins induced complete tumor inhibition.…”

Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 99%

“…Even though ZK 98299 showed less antiglucocorticoid activity than RU486, it had to be withdrawn from the market because of liver toxicity (Klijn et al 2000). Interestingly, when PR-B is activated by high levels of cAMP, RU486 acts as an agonist (Horwitz 1992, Baulieu 1997, thus stimulating cell proliferation.…”

Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Lanari¹,

Lamb²,

Fabris³

et al. 2009

Endocrine-Related Cancer

101

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More than 60% of all breast neoplasias are ductal carcinomas expressing estrogen (ER) and progesterone receptors (PR). By contrast, most of the spontaneous, chemically or mouse mammary tumor virus induced tumors, as well as tumors arising in genetically modified mice do not express hormone receptors. We developed a model of breast cancer in which the administration of medroxyprogesterone acetate to BALB/c female mice induces mammary ductal carcinomas with a mean latency of 52 weeks and an incidence of about 80%. These tumors are hormone-dependent (HD), metastatic, express both ER and PR, and are maintained by syngeneic transplants. The model has been further refined to include mammary carcinomas that evolve through different stages of hormone dependence, as well as several hormone-responsive cell lines. In this review, we describe the main features of this tumor model, highlighting the role of PR as a trigger of key signaling pathways mediating tumor growth. In addition, we discuss the relevance of this model in comparison with other presently used breast cancer models pointing out its advantages and limitations and how, this model may be suitable to unravel key questions in breast cancer.

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Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 75%

Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 99%

Section: Estrogen and Antiprogestin In Breast Cancer Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Lanari¹,

Lamb²,

Fabris³

et al. 2009

Endocrine-Related Cancer

101

View full text Add to dashboard Cite

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“…Early progesterone antagonists showed greater antitumor activity than tamoxifen or high-dose progesterone agonists and synergized with antiestrogens (Klijn et al, 2000). Clinical data are meager but at least 5 studies have used antiprogestins in women with breast cancer.…”

Section: Prms In Breast Cancer Trialsmentioning

confidence: 99%

Progesterone receptor modulators in breast cancer

Wiehle¹,

2014

Turk J Biol

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Breast cancer has been treated successfully with selective estrogen receptor antagonists (SERMs) such as tamoxifen, receptordepleting agents such as fulvestrant, and aromatase inhibitors such as anastrozole. Selective progesterone receptor modulators (SPRMs or PRMs) have not been studied as much and are currently under investigation for inhibition of mammary carcinogenesis in animal models and breast cancer prevention trials in women. They might follow tamoxifen and aromatase inhibitors in the adjuvant treatment of breast cancers with acquired resistance. These uses have not provoked ground-breaking progress or studies and PRMs do not have a high profile. Most in vitro and in vivo studies indicate that PRMs preferentially suppress cell proliferation and also induce apoptosis. In this review we summarized the data on the effects of PRMs and particularly of the antiprogestins RU-486 (mifepristone) and CDB-4124 (Progenta, Proellex or telapristone acetate) on breast cancer models. Both agents have been employed in preclinical and clinical studies for prevention and treatment of breast cancer. This author believes that PRMs should be investigated more intensely.

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“…Previous studies have shown that RU-486 at high doses can elevate serum estradiol and progesterone levels, impacting endometrial cell proliferation (22). Data from several clinical trials in patients with advanced breast cancer treated with RU-486 or onapristone, another antiprogestin, have shown a favorable response in 10% to 12% of the patients and stable disease in 42% to 46% of the patients (23). The combination of PR antagonists (mifepristone, ORG 31710, onapristone) with antiestrogens (tamoxifen, raloxifene, ICI 164384) or with aromatase inhibitors (atemestane) showed greater antitumor efficacy than when given alone, suggesting potential clinical efficacy in patients resistant to long-term therapy with tamoxifen (23).…”

Section: Introductionmentioning

confidence: 99%

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

Wiehle

Lantvit

Yamada

et al. 2011

Cancer Prevention Research

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CDB-4124 (Proellex or telapristone acetate) is a modulator of progesterone receptor (PR) signaling, which is currently employed in preclinical studies for prevention and treatment of breast cancer and has been used in clinical studies for treatment of uterine fibroids and endometriosis. Here we provide evidence for its action on steroid hormone-signaling, cell cycle-regulated genes and in vivo on mammary carcinogenesis. When CDB-4124 is given to rats at 200 mg/kg for 24 months, it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. Also, CDB-4124 given as subcutaneous pellets at two different doses suppressed, dose dependently, N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis. The high dose (30 mg, over 84 days) increased tumor latency from 66 AE 24 days to 87 AE 20 days (P < 0.02), decreased incidence from 85% to 35% (P < 0.001), and reduced multiplicity from 3.0 to 1.1 tumors/animal (P < 0.001). Tumor burden decreased from 2.6 g/animal to 0.26 g/animal (P < 0.01). CDB-4124 inhibited cell proliferation and induced apoptosis in MNU-induced mammary tumors, which correlated with a decreased proportion of PR þ tumor cells and with decreased serum progesterone. CDB-4124 did not affect serum estradiol. In a mechanistic study employing T47D cells we found that CDB-4124 suppressed G 1 /G 0 -S transition by inhibiting CDK2 and CDK4 expressions, which correlated with inhibition of estrogen receptor (ER) expression. Taken together, these data indicate that CDB-4124 can suppress the development of precancerous lesions and carcinogen-induced ER þ mammary tumors in rats, and may have implications for prevention and treatment of human breast cancer. Cancer Prev Res; 4(3); 414-24. Ó2011 AACR.

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Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer

Cited by 140 publications

References 27 publications

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer

Progesterone receptor modulators in breast cancer

CDB-4124, a Progesterone Receptor Modulator, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation and Inducing Apoptosis

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