Labrie F
Molecular Endocrinology and Oncology Research Center, Laval University Hospital Research Center (CRCHUL) and Laval University, 2705, Laurier Boulevard, Quebec City, Quebec G1V 4G2, Canada.
Endocr Relat Cancer. 2006 Jun;13(2):335-55. doi: 10.1677/erc.1.00883.
Breast cancer is the most frequently diagnosed and the second cause of cancer death in women, thus making breast cancer a most feared disease. Since breast cancer metastasizes early and it is unlikely that improvements in the treatment of metastatic disease could permit a cure in most cases in the foreseeable future, it is clear that prevention is essential in order practically to eliminate deaths from breast cancer. Tamoxifen is the only selective estrogen receptor modulator (SERM) currently registered for use in breast cancer prevention; the tamoxifen versus raloxifene study should indicate the efficacy of this compound compared with raloxifene. The recent benefits of aromatase inhibitors over tamoxifen indicate the advantages of a blockade of estrogens more complete than the one achieved with tamoxifen, a SERM having some estrogenic activity in the mammary gland and an even higher estrogenic action in the uterus. However, it is unlikely that the general estrogen ablation achieved with aromatase inhibitors will be acceptable for the long-term use required for prevention. It is thus important to develop SERMs with highly potent and pure antagonistic activity in the mammary gland and uterus while possessing estrogen-like activity in tissues of particular importance for women's health, namely the bones and the cardiovascular system. However, it is expected that a SERM alone will not meet all the requirements of women's health at the postmenopause when ovarian estrogen secretion has ceased and peripheral formation of androgens and estrogens from DHEA by intracrine mechanisms is decreased by 60% or more. One possibility is to combine a SERM with DHEA, a precursor of sex steroids that permits, somewhat like SERMs, tissue-specific formation of androgens and/or estrogens according to the level of expression of the steroidogenic and steroid-inactivating enzymes. DHEA could thus compensate for the important loss of androgens that accompanies aging and could also permit sex steroid formation and action in the brain while breast cancer prevention would be achieved by the SERM.
乳腺癌是女性中最常被诊断出的癌症，也是癌症死亡的第二大原因，因此乳腺癌成为一种令人最为恐惧的疾病。由于乳腺癌早期就会发生转移，而且在可预见的未来，转移性疾病治疗方面的改善在大多数情况下不太可能实现治愈，显然预防对于切实消除乳腺癌死亡至关重要。他莫昔芬是目前唯一注册用于预防乳腺癌的选择性雌激素受体调节剂（SERM）；他莫昔芬与雷洛昔芬的研究应能表明该化合物与雷洛昔芬相比的疗效。芳香化酶抑制剂相对于他莫昔芬的近期优势表明，与他莫昔芬相比，阻断雌激素更为彻底具有优势，他莫昔芬这种SERM在乳腺中具有一定雌激素活性，在子宫中具有更高的雌激素作用。然而，芳香化酶抑制剂实现的全身性雌激素消除不太可能被接受用于预防所需的长期使用。因此，开发在乳腺和子宫中具有高效和纯拮抗活性，同时在对女性健康特别重要的组织即骨骼和心血管系统中具有类雌激素活性的SERM非常重要。然而，预计在绝经后卵巢雌激素分泌停止且通过内分泌机制从脱氢表雄酮（DHEA）外周生成雄激素和雌激素减少60%或更多时，单独一种SERM将无法满足女性健康的所有需求。一种可能性是将一种SERM与DHEA联合使用，DHEA是性类固醇的前体，它有点像SERM，能根据类固醇生成和类固醇失活酶的表达水平实现组织特异性雄激素和/或雌激素的生成。DHEA因此可以补偿伴随衰老而来的雄激素的重要损失，还能在大脑中实现性类固醇的生成和作用，而SERM则可实现乳腺癌预防。
