Estrogen-responsive breast cancers

Twenty-four cyclopropyl compounds were screened for their antiproliferative activities, eighteen were found to be active and five appeared to be promising pure antiestrogens, superior to tamoxifen 128 not only in the treatment of the estrogen-dependent tamoxifen-responsive breast cancer patients, but also in the treatment of the estrogen-independent, tamoxifen non-responsive, breast cancer patients. 

Most steroid-sensitive cancers express specific cell surface receptors. Prednisone-sensitive lymphomas, estrogen-sensitive breast cancers, and prostatic cancers express specific receptors for corticosteroids, estrogens, and androgens, respectively. It is now possible to assay tumor specimens for steroid receptor content and to identify which individual patients are likely to benefit from hormonal therapy. Measurement of the estrogen receptor (ER) and progesterone receptor (PR) proteins in breast cancer tissue is now standard clinical practice. ER or PR positivity predicts response to hormonal therapy, whereas patients whose tumors are ER-negative generally fail to respond to such treatment. 

Bo TTA and EPA have been shovm to be inhibitors of growth of human breast cancer cells in culture. " TTA was found to have the most potent inhibitory effect on the estrogen responsive human cancer epithelial cell line MCF-7. 

Another type of fluorescent steroid was used as a probe for the estrogen receptor. This receptcn- plays a role in the growth of hormone-responsive breast cancers, and analysis of receptor levels is an important aspect in the treatment of breast cancer. Estradiol is not fluorescent, so it cannot be... 

The measurement of ER has become a standard assay in the clinical management of breast cancer. The presence of ERa identifies those breast cancer patients with a lower risk of relapse and better clinical outcome. Receptor status also provides a guideline for those tumors that may be responsive to hormonal intervention. But only about half of ER-positive patients respond to hormonal therapies. Of those who respond initially, most will eventually develop an estrogen unresponsive disease following a period of treatment even though ERa is often still present. Mutant receptors and constitutively active r eceptors as well as hormone-independent activation of the ERa are discussed. The involvement of ER 3 isoforms is under investigation. 

The test system was considerably less sensitive to endosulfan when mouse ER, rather than human ER, was used to mediate (3-gal activity (Ramamoorthy et al. 1997). In similar assays, endosulfan at 10 jM had no effect on (3-gal activity in yeast Saccharomyces) transfected with either the human or rainbow trout ER (Andersen et al. 1999). In addition, no effect was observed on transcriptional activation of HeLa cells transfected with plasmids containing an estrogen receptor as a responsive element (Shelby et al. 1996). Endosulfan also did not induce transient reporter gene expression in MCF-7 human breast cancer cells at an incubation concentration of 2.5 pM (Andersen et al. 1999). Maximum endosulfan-induced ER-mediated luciferase reporter gene expression occurred in vitro in a T47D human breast adenocarcinoma cell line at approximately 10 pM, while 50% expression of luciferase occurred at about 5.9 pM the maximum expression was approximately 59% of the effect from exposure to 0.03 nM estradiol (0.00003 pM) (Legler et al. 1999). Luciferase expression from combined treatment with endosulfan and dieldrin was additive over concentrations ranging from 3 to 8 pM. 

Seiler-Tuyns A, Walker P, Martinez E, Merillat AM, Givel F, Wahli W (1986) Identification of estrogen-responsive DNA sequences by transient expression experiments in a human breast cancer cell line. Nucleic Acids Res 14 8755... 

Trioxifene is an older SERM with low estrogenic properties and a higher affinity for ER than tamoxifen. It has shown an unfavorable safety profile in clinical studies of women with breast cancer (leukopenia in 41% of patients, nausea in 31%) (Witte et al. 1986), which is why, in addition to its response rates being no better than in tamoxifen (Lee et al. 1986), its clinical development has been cancelled. 

Fisher B, Redmond C, Brown A, Wickerham DL, Wolmark N, Allegra J, Escher G, Lipp-man M, Savlov E, Wittliff J, et al. (1983) Influence of tumor estrogen and progesterone receptor levels on the response to tamoxifen and chemotherapy in primary breast cancer. J Clin Oncol 1(4) 227—241... 

Experimental studies showed antitumoral effects of raloxifene in different in vitro preparations and animal models. Raloxifene has been able to inhibit the mitogenic effect induced by estrogens on ZR-75-1 cells, an estrogen responsive human breast cancer cell line (Poulin et al. 1989). In a well-accepted rat model of breast cancer induced by nitroso-methyl urea (NMU) raloxifene significantly suppressed the development of breast tumors and acted synergistically with 9 cis-retinoic acid (Anzano et al. 1996). 

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