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  • In conclusion the present study demonstrates


    In conclusion, the present study demonstrates that E2's antiapoptotic effects are significantly reduced by coadministration of progestogens. The combination of E2 and progestogens resulted in diverging effects on the expressions of ERs and PRs, which induced different effects on the cell growth of MCF-7 cells. Our results in the MCF-7 TG003 showed that E2-abrogating apoptosis is mediated by ERα and that the regulated expression of PRA and PRB is critical to the breast cells' response to synthetic progesterone. The effect of P4 on breast cells and the expression of ERs and PRs are different from that of synthetic progestins. Thus, the present study reveals that aberrant hormone activity, by way of altered receptor expression, may be an important factor in the malignant transformation of breast cells.
    Acknowledgments This study was supported by the Medical Research Center (Chang Gung Memorial Hospital, Keelung) and a research grant from the Clinical Monitoring Research Program (CMRPG280072) of Chang Gung Memorial Hospital, Keelung.
    Introduction Breast cancer causation has been linked to repeated exposure of the breast to estrogen and progesterone, producing waves of epithelial proliferation in the luteal phase of the menstrual cycle [1], [2], [3], [4]. More sustained exposure with estrogen plus MPA increases breast cancer risk to a greater extent than estrogen alone in postmenopausal women [5], [6], as do progestin-based contraceptives in premenopausal women [7], [8], [9]. Moreover, the tumors seen with the use of depot MPA and combined hormone therapy appear to be more aggressive [8], [10]. Additionally, MPA and progesterone augment tumor formation in DMBA-treated rats [11]. Concomitantly, the role of PR in breast carcinogenesis is increasingly recognized [12], [13], [14]. These data point to PR blockade as an excellent (but clinically untested) strategy for breast cancer prevention. Second generation anti-progestins are under development for the treatment of benign gynecological conditions [13], [15], [16], [17], thereby providing robust toxicity data for the design of breast cancer prevention trials [13], [16], [18], [19]. These agents differ from mifepristone (RU486) and onapristone, which were tested in postmenopausal metastatic breast cancer patients, but caused liver toxicity and anti-glucocorticoid effects [20], [21], [22], [23]. The second generation anti-progestins are potent, and preserve PR selectivity while reducing the ‘off-target’ effects on glucocorticoid receptor (GR), and androgen receptor (AR), which are seen with mifepristone [24], [25], [26], [27]. Among these, TPA (CDB-4124) and UPA (CDB-2914) have attracted attention as potential breast cancer treatment and prevention agents, based on preclinical efficacy data [25], [26], [28], [29], [30] and a good safety profile. Additional rationale for a focus on prevention derives from data pointing to involvement of the progesterone-pathway in early steps in cancer development [12], [13], [14]; in contrast, the data on the treatment of an advanced disease are confusing, since high doses of megestrol acetate [31], [32], [33] and MPA [34], [35] have therapeutic efficacy–this finding is similar to high dose estrogen (HDE) [36], [37]. Previous studies show that TPA significantly delays the growth of established DMBA-induced mammary tumors and delays tumor onset in MNU-treated rats [28], [29]. We now report experiments addressing the anti-cancer efficacy of TPA in rodents exposed to carcinogens plus progestogens (MPA or progesterone), and growth suppression of T47D spheroids grown in physiological estradiol and progesterone concentrations. Our goal was to develop biomarkers of response for use in our ongoing trials ( NCT01800422 and NCT02314156), and test the hormonal conditions under which anti-progestins are effective in repressing tumor cell growth. We confirm prior studies suggesting that both proliferation and angiogenesis are decreased by anti-progestins [29], and find that TPA, UPA, and mifepristone are effective in suppressing the growth of T47D spheroids in both premenopausal and postmenopausal hormone conditions.