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  • Finally we demonstrated for the first time that the physiolo


    Finally, we demonstrated for the first time that the physiological combinations of estradiol and progesterone levels of premenopausal and postmenopausal women efficiently stimulated the growth of T47D spheroids while clinically relevant concentrations of TPA and UPA suppressed the growth of T47D spheroids equally or even better than mifepristone. These findings suggest that TPA and UPA could be more potent inhibitors for ER/PR positive breast cancer than mifepristone since mifepristone exerts considerable anti-glucocorticoid effects through GR binding. Although T47D DCG IV have very high PR expression that may not be relevant to the majority of breast cancers, encouraging data regarding the efficacy of UPA have been recently studied in several cell models [30], [62] and in patient-derived breast cancer xenografts [61]. Additionally, we have completed a pre-surgical window trial in women using TPA with ER positive or PR positive primary breast cancer. Thus the data are beginning to accumulate, which support the continued clinical evaluation of this class of agents for breast cancer treatment and prevention. The importance of progesterone/progestin effects in the promotion of breast cancer has been discussed by several authors recently [63], [64], [65], [66], including debate as to whether progesterone action in the mammary gland is carcinogenic or protective. Progesterone in the presence of estradiol (as in the luteal phase of the menstrual cycle) clearly induces a mitotic wave in normal breast cells [67], [68]; recent data support the notion that increased cell proliferation induced by progestogens aids tumor development [63]. Additionally, the pro-tumorigenic effects of progesterone exposure may include expansion of the stem cell pool, which has been observed in the normal mouse mammary gland and human breasts [69], [70], [71]. Interestingly, recent data indicate that progesterone and MPA influence a stem cell phenotype (CK5+) in T47D xenograft tumors [72]. These data are countered by a recent report by Mohammed et al., showing that progesterone and R5020 inhibit the growth of estrogen-dependent primary ER positive breast tumors ex vivo and growth of MCF-7 cell xenografts in vivo [73]. However, they used a very high concentration of R5020 (10-fold higher than typically used in culture), which may have contributed to their observation of tumor growth inhibition in the presence of high estradiol, similar to the effects of HDE and high dose PR agonists. These data highlight again the need to distinguish early from late models of cancer, since progesterone may have a biphasic effect [74], and its effect may be time and dose-dependent.
    Conflict of interest
    Acknowledgements This work was supported by Breast Cancer Research Foundation for the MNU/rat study and spheroid experiment and Lynn Sage Cancer Research Foundation for the DMBA/mouse study. The authors would like to thank Repros Therapeutics, Inc., and HRA-Pharma (Paris, France) for providing materials and other support. The authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the writing of the manuscript, and the decision to submit the manuscript for publication.
    Introduction Androgen receptor (AR) and progestogen receptor (PR) are ligand-dependent transcriptional factors that belong to a large family of nuclear receptors. Members of the nuclear receptor superfamily, such as retinoid X receptor and thyroid hormone receptor, possess multiple subtypes and isoforms in mammals (Mangelsdorf et al., 1995). In the present article, the term ‘isoforms’ describes variants derived from translational initiation at multiple in-phase ATG codons, alternative splicing, or species-specific tetraploidy, whereas the term ‘subtypes’ is used for distinct gene products, considered to be paralogues. It has been proposed by many authors that two rounds of whole genome duplication occurred early in the vertebrate lineage and their genome contains four fold more gene loci than the invertebrate genome (Ohno, 1970, Sidow, 1996, Baker, 1997, Spring, 1997, Pebusque et al., 1998, Whitfield et al., 1999). Their four related genes, considered to be derived from one ancestral invertebrate homologue, are thought to be paralogues.