Hypoxia reduces hormone responsiveness of human breast cancer cells.
Hypoxia reduces hormone responsiveness of human breast cancer cells.
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DOI：
10.1111/j.1349-7006.2001.tb01064.x
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发表时间：
2001-10
期刊：
影响因子：
--
通讯作者：
Sonoo H
中科院分区：
文献类型：
--
作者：
Kurebayashi J;Otsuki T;Moriya T;Sonoo H
在乳腺癌的成功治疗后，激素治疗的抵抗经常发生。导致这种获得性耐药性的机制仍不清楚。有人认为，低氧的肿瘤微环境促进了癌症的恶性进展，即低氧可能促进乳腺癌的雌激素非依赖性生长(一种更恶性的表型)。为了阐明这一假说，我们研究了低氧对两种人乳腺癌细胞株ML-20和KPL-1的生长反应以及雌激素受体(ER)-α和孕激素受体(PgR)表达水平的影响。低氧(1%O2)可显著降低这两种细胞中ER-α的表达水平，且呈时间依赖性。在这两种细胞中，低氧也显著降低了雌二醇(E2)的促生长作用和抗雌激素ICI 182 780和孕激素(甲孕酮醋酸酯)的生长抑制作用。此外，低氧显著抑制了E2对两种细胞中PGR基因和蛋白的诱导。为进一步阐明缺氧对ER-α表达的影响，采用免疫组织化学方法检测了36例乳腺癌组织中缺氧标志物缺氧诱导因子-1α(HIF-Lα)和ER-α的表达水平。ER-α在核HIF-Lα阳性肿瘤中的表达比例和强度均显著低于阴性肿瘤。这些结果表明，低氧下调了乳腺癌细胞ER-α的表达和ER-α的功能。这些过程可能导致乳腺癌患者对激素治疗产生获得性抵抗。
Resistance to hormonal therapy frequently occurs following successful treatment in breast cancer. The mechanism responsible for this acquired resistance is still unknown. It has been suggested that a hypoxic tumor microenvironment promotes malignant progression of cancer, i.e., hypoxia may promote estrogen‐independent growth (a more malignant phenotype) of breast cancer. To clarify this hypothesis, the effects of hypoxia on the growth responses to hormonal agents and the expression levels of estrogen receptor (ER)‐α and progesterone receptor (PgR) were investigated in two human breast cancer cell lines, ML‐20 and KPL‐1. The expression level of ER‐α was significantly decreased by hypoxia (1% O2) in a tune‐dependent manner in both cell lines. Hypoxia also significantly reduced the growth‐promoting effect of estradiol (E2) and the growth‐inhibitory effects of an antiestrogen, ICI 182 780, and a progestin, medroxyprogesterone acetate, in both cell lines. In addition, hypoxia markedly suppressed the induction of PgR mRNA and protein by E2 in both cell lines. To clarify further the effect of hypoxia on ER‐α expression, the expression levels of hypoxia‐inducible factor‐la (HIF‐lα), a marker of hypoxia and ER‐α were immunohistochemically examined in 36 breast cancer specimens. ER‐α expression (both its proportion and intensity) was significantly lower in nuclear HIF‐lα‐positive tumors than in negative tumors. These findings indicate that hypoxia down‐regulates ER‐α expression as well as ER‐α function in breast cancer cells. These processes may lead to an acquired resistance to hormonal therapy in breast cancer
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