In situ estrogen production and its regulation in human breast carcinoma: From endocrinology to intracrinology
In situ estrogen production and its regulation in human breast carcinoma: From endocrinology to intracrinology
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DOI：
10.1111/j.1440-1827.2009.02444.x
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发表时间：
2009-11
影响因子：
2.2
通讯作者：
H. Sasano;Y. Miki;S. Nagasaki;Takashi Suzuki
中科院分区：
文献类型：
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作者：
H. Sasano;Y. Miki;S. Nagasaki;Takashi Suzuki
绝经后妇女发生的绝大多数乳腺癌是雌激素依赖或癌细胞雌激素受体（ER）阳性，尽管血浆或循环雌激素浓度明显较低。在这些患者中，生物活性雌激素是由乳腺癌组织内循环的非活性类固醇（包括肾上腺雄激素）局部产生的，并赋予癌细胞雌激素活性。一系列的酶参与了乳腺癌组织中肿瘤内或原位雌激素的产生，但芳香化酶是细胞色素P450家族的一员，是雌激素依赖性绝经后乳腺癌中通过循环肾上腺雄激素转化产生雌激素的关键酶。确定雌激素产生的部位就变得很重要了。然而，关于芳香化酶在乳腺癌肿瘤内的定位一直存在争议，特别是通过芳香化酶在肿瘤内产生雌激素是发生在癌细胞还是间质细胞中。该酶在乳腺癌组织的癌细胞和间质细胞中均有表达，免疫组织化学检测结果为单克隆抗体677，激光捕获显微解剖/定性逆转录-聚合酶链反应相结合。这两种细胞类型的瘤内芳香化酶随后被证明是由与乳腺癌浸润相关的癌间质相互作用诱导的。通过各种核受体的信号，特别是癌细胞中的雌激素相关受体α和癌浸润附近脂肪细胞中的肝受体同源物- 1，与各种细胞因子和/或生长因子一起，在诱导肿瘤内芳香化酶的过程中起关键作用。这种增加的芳香化酶随后导致乳腺癌原位雌激素浓度增加。芳香化酶抑制剂目前被确立为治疗雌激素受体阳性乳腺癌的金标准，但对该疗法的耐药性仍有待于通过抑制肿瘤内雌激素产生的其他模式来解决。
The great majority of breast carcinomas arising in postmenopausal women are estrogen dependent or positive for estrogen receptor (ER) in carcinoma cells despite markedly low plasma or circulating estrogen concentrations. In these patients, biologically active estrogens are locally produced from circulating inactive steroids including adrenal androgens in an intracrine mechanism in the breast cancer tissues and confer estrogenic activities on carcinoma cells. A series of enzymes are involved in this intra‐tumoral or in situ production of estrogens in breast carcinoma tissues but aromatase, a member of the cytochrome P450 family, is a key enzyme of estrogen production through conversion from circulating adrenal androgens in estrogen‐dependent postmenopausal breast cancer. It then becomes important to identify the sites of this estrogen production. There has been, however, controversy regarding intra‐tumoral localization of aromatase in breast carcinoma, especially whether intra‐tumoral production of estrogens through aromatase occurs in carcinoma or stromal cells. The enzyme was demonstrated to be expressed in both carcinoma and stromal cells in breast carcinoma tissues on immunohistochemistry with a well‐characterized mAb 677 and combined laser capture microdissection/qualitative reverse transcriptase–polymerase chain reaction. Intra‐tumoral aromatase in both of these cell types was subsequently demonstrated to be induced by carcinoma–stromal interactions associated with carcinoma invasion in breast tissue. The signals through various nuclear receptors, especially estrogen‐related receptor‐α in carcinoma cells and liver receptor homologue‐1 in adipocytes adjacent to carcinoma invasion, in conjunction with various cytokines and/or growth factors, play pivotal roles in this induction of intra‐tumoral aromatase. This increased aromatase subsequently results in increased in situ estrogen concentrations of breast cancer. Aromatase inhibitors are currently established as the gold standard for the treatment for ER‐positive breast carcinoma but resistance to the therapy still remains to be solved by other modes of suppression of intra‐tumoral estrogen production.