The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology

Engman, Mikael; Skoog, Lambert; Söderqvist, Gunnar; Gemzell‐Danielsson, Kristina

doi:10.1093/humrep/den228

Cited by 61 publications

(32 citation statements)

References 27 publications

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“…Furthermore, both MPA and P have been found to reactivate stem cells with potential for malignancy, in vitro, but the clinical implications of this finding for women are not elucidated (29). Recently we reported that so far the only antiproliferative drug in normal breast tissue in vivo is the anti-P mifepristone, which significantly reduced breast cell proliferation in premenopausal women (30).…”

mentioning

confidence: 99%

Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women

Murkes¹,

Conner²,

Leifland³

et al. 2011

Fertility and Sterility

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Effects of percutaneous estradiol-oral progesterone versus oral conjugated equine estrogens-medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy womenIn a prospective, randomized clinical study 77 women were assigned randomly to receive sequential hormone therapy with either conventional oral conjugated equine estrogens (0.625 mg) with the addition on 14 of the 28 days of oral medroxyprogesterone acetate (5 mg) or natural E 2 gel (1.5 mg) with oral micronized P (200 mg) on 14 of the 28 days of each cycle. Because oral conjugated equine estrogens-medroxyprogesterone acetate induced a highly significant increase in breast cell proliferation in contrast to percutaneous E 2 -oral P with a difference between therapies approaching significance, the former therapy has a marked impact on the breast whereas natural percutaneous E 2 -oral micronized P has not. (Fertil Steril Ò 2011;95:1188-91. Ó2011 by American Society for Reproductive Medicine.)Key Words: Percutaneous estradiol, micronized progesterone, HT, proliferation, bcl-2 protein, normal breast tissue Postmenopausal hormone therapy (HT) has been associated with an increased risk for breast cancer. The risk with combined estrogen-progestogen therapy is greater than with estrogen alone (1-6). Hormone therapy is not a uniform concept, and various preparations, doses, and regimens of HT may have different effects (7). Although estrogen is a known mitogen in the breast, the effects of added progestogens may vary considerably (8-15), but proliferative responses are seen within 2 months (9-11). Synthetic progestogens may differ from natural P. In the French E3N cohort, women taking estrogen in combination with micronized P were found to have no increase in breast cancer risk in contrast to women taking estrogen in combination with synthetic progestogens (16,17).In this study we used core needle biopsy to evaluate breast cell proliferation in healthy postmenopausal women during two different types of sequential HTs: oral conjugated estrogens plus synthetic progestogen versus percutaneous E 2 plus natural oral micronized P. A prospective randomized clinical study was performed at the Karolinska University Hospital, Stockholm, Sweden, between May 2006 and March 2008. Apparently healthy women, aged 44 to 66 years, postmenopausal for at least 12 months, nonsmokers, with normal mammogram results, and with a body mass index of 18 to 30 kg/m 2 , were recruited. Follicle-stimulating hormone levels at screening were >25 IU/L, and E 2 levels <90 pmol/L. The washout period for previous HT users was 3 months.Exclusion criteria were any breast disease, previous breast surgery, hepatic dysfunction, active gallbladder disease, or history of thromboembolic disease. Medication with sexual steroids, barbiturates, carbamazepines, phenytoin, glucocorticoids, rifampicin, cimetidine, diltiazem, erythromycin, ketoconazole, verapamil, and quinidine was not permitted.

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confidence: 99%

Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women

Murkes¹,

Conner²,

Leifland³

et al. 2011

Fertility and Sterility

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“…The inhibitory effect of CDB-4124 on cell proliferation we see in both, long-and short-term (3 month) treatments correlates well with recent data from a clinical trial with mifepristone (RU-486). Women with leiomyoma, treated with 50 mg RU-486 every second day for 3 months, underwent fine-needle breast biopsies before initiation and after termination of treatment (5). A significant reduction in proliferating breast epithelial cells (Ki-67-positive) were observed in RU-486-treated versus placebo-treated patients, suggesting that antiprogestin treatment can prevent the development and progression of ER þ and PR þ breast cancer by inhibiting MEC proliferation.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…It is generally accepted that progesterone receptor (PR) is an estrogen-regulated gene and its synthesis in normal and tumor cells requires estrogen and estrogen receptor (ER; refs. 4,5). As a result of endocrine therapy with tamoxifen, ER and PR in breast cancer cells may decrease, but complete loss of receptor does not occur (6)(7)(8).…”

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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“…Women with leiomyoma treated with 50 mg of RU-486 every second day for 3 months underwent fine needle breast biopsies before initiation and after termination of treatment (Engman et al, 2008). A significant reduction in proliferating breast epithelial cells (Ki-67 positive) was observed in RU-486 treated vs. placebo treated patients, suggesting that antiprogestin treatment can prevent the development and progression of ER+ and PR+ breast cancer by inhibiting mammary epithelial cell proliferation.…”

Section: Cellular Mode Of Action: Mammary Proliferation and Apoptosismentioning

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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The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology

Cited by 61 publications

References 27 publications

Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women

Effects of percutaneous estradiol–oral progesterone versus oral conjugated equine estrogens–medroxyprogesterone acetate on breast cell proliferation and bcl-2 protein in healthy women

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

Progesterone receptor modulators in breast cancer

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