Falany J L, Falany C N
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.
Oncol Res. 1997;9(11-12):589-96.
Estrogen metabolism is closely associated with the growth, progression, and treatment of breast cancer because many breast cancers are dependent upon estrogens for both growth and progression. Factors that affect the intracellular metabolism of estrogens may be critical in altering the effects of estrogens on breast cancer cells. MCF-7 cells have been used as a model system to study the effects of estrogens on breast cancer cellular growth. Because normal human mammary epithelial (HME) cells contain estrogen sulfotransferase (EST), which is involved in the inactivation of estrogens via sulfation, and MCF-7 cells do not possess this enzyme, the absence of EST may be critical to the growth of MCF-7 cells in the presence of estrogens. To study the effects of EST on cellular growth, MCF-7 cells stably transformed with an EST expression vector were compared to control cells transformed with vector only. Sulfation of 20 nM E2 occurs more rapidly with MCF-7 cells transformed with EST than with the control cells, thereby rendering E2 physiologically inactive. Additionally, these EST/MCF-7 cells sulfate 20 nM 17 alpha-ethinylestradiol (EE2) at a rate similar to that for E2 but sulfate 20 nM diethylstibestrol (DES) much more slowly; these results correlate with the kinetic characteristics of EST for these steroids. EST/MCF-7 cells require higher concentrations of E2 to stimulate growth than do control MCF-7 cells, hypothetically because EST is inactivating E2 via sulfation, rendering it incapable of binding to the estrogen receptor (ER). The effects of EE2 are similar to those of E2 whereas DES is effective at lower concentrations because it is not inactivated by EST. Neither control nor EST/MCF-7 cells grow well in the complete absence of estrogens, as would be expected because MCF-7 cells are estrogen dependent. However, in medium that has not been treated to remove endogenous estrogens, EST/MCF-7 cells grow more slowly than control cells, most likely because EST is inactivating the estrogens in the medium, making them ineffective in stimulating growth. EST/MCF-7 cells possess EST at levels similar to HME cells and are less responsive to estrogens than are MCF-7 cells lacking EST. The loss of EST may be a factor in oncogenesis, which leads to altered estrogen metabolism in breast carcinoma cells.
雌激素代谢与乳腺癌的生长、进展及治疗密切相关，因为许多乳腺癌的生长和进展都依赖于雌激素。影响雌激素细胞内代谢的因素可能在改变雌激素对乳腺癌细胞的作用方面起着关键作用。MCF - 7细胞已被用作研究雌激素对乳腺癌细胞生长影响的模型系统。由于正常人类乳腺上皮（HME）细胞含有雌激素磺基转移酶（EST），该酶通过硫酸化参与雌激素的失活，而MCF - 7细胞不具备这种酶，因此在有雌激素存在的情况下，EST的缺失可能对MCF - 7细胞的生长至关重要。为了研究EST对细胞生长的影响，将用EST表达载体稳定转化的MCF - 7细胞与仅用载体转化的对照细胞进行比较。与对照细胞相比，用EST转化的MCF - 7细胞对20 nM E2的硫酸化发生得更快，从而使E2失去生理活性。此外，这些EST/MCF - 7细胞以与E2相似的速率硫酸化20 nM 17α - 乙炔雌二醇（EE2），但硫酸化20 nM己烯雌酚（DES）的速率要慢得多；这些结果与EST对这些类固醇的动力学特征相关。与对照MCF - 7细胞相比，EST/MCF - 7细胞需要更高浓度的E2来刺激生长，推测是因为EST通过硫酸化使E2失活，使其无法与雌激素受体（ER）结合。EE2的作用与E2相似，而DES在较低浓度下有效，因为它不会被EST失活。正如预期的那样，由于MCF - 7细胞依赖雌激素，在完全没有雌激素的情况下，对照细胞和EST/MCF - 7细胞都生长不佳。然而，在未经过处理以去除内源性雌激素的培养基中，EST/MCF - 7细胞比对照细胞生长得更慢，最可能的原因是EST使培养基中的雌激素失活，使其在刺激生长方面无效。EST/MCF - 7细胞中EST的水平与HME细胞相似，并且比缺乏EST的MCF - 7细胞对雌激素的反应性更低。EST的缺失可能是肿瘤发生的一个因素，这导致乳腺癌细胞中的雌激素代谢发生改变。
