Kuijper T Martijn, Ruigrok-Ritstier Kirsten, Verhoef-Post Miriam, Piersma Djura, Bruysters Martijn W P, Berns Els M J J, Themmen Axel P N
Department of Internal Medicine, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Mol Cell Endocrinol. 2009 Apr 10;302(1):58-64. doi: 10.1016/j.mce.2008.12.016. Epub 2009 Jan 20.
Worldwide, breast cancer is the most frequently occurring malignancy in women. Early age at full term pregnancy has a protective effect against breast cancer. Evidence coming from a rat breast cancer model suggests a possible role for the pregnancy hormone hCG, a ligand of the LH receptor, as a mediator for this effect. In a previous study, we found that a common polymorphism in the LH receptor associates with tumor progression in premenopausal breast cancer patients, as carriers of the variant receptor showed a shorter disease free survival compared to non-carriers. How hCG and its receptor exert their effects on breast cancer, however, is unclear. One possibility is that these effects take place through LH receptors present in the ovaries, thereby influencing steroid hormone production. Another possibility is that the effects take place through LH receptors present in breast tumor cells themselves, as some studies have detected the receptor in both normal and neoplastic breast tissues and in breast cancer cell lines. To investigate whether a direct effect of LH signaling in breast cancer is likely, we measured LH receptor mRNA expression levels in 1551 breast tumors and 42 different human breast cancer cell lines using a qRT-PCR with a wide dynamic range. In addition, associations between LH receptor expression and clinico-pathologic factors were investigated. Assay validation showed that as little as ?10 copies per reaction volume of LH receptor cDNA could still be detected by our assay. We show that LH receptors are undetectable in 62% of breast tumor samples and 41 of 42 breast cancer cell lines. For the remaining samples we found expression levels to be very low. Although low, expression of the LH receptor appears to be associated with normal breast cells, favorable tumor characteristics and low tumor percentage. Since expression of the LH receptor in breast cancer cells is very low, it almost excludes the possibility of direct signaling effects. We therefore conclude that signaling effects of the LH receptor on breast cancer most likely take place by an indirect pathway through the ovaries.
在全球范围内，乳腺癌是女性中最常见的恶性肿瘤。足月妊娠年龄较早对乳腺癌具有保护作用。来自大鼠乳腺癌模型的证据表明，妊娠激素hCG（促黄体生成素受体的配体）可能作为这种效应的介导物发挥作用。在先前的一项研究中，我们发现促黄体生成素受体中的一种常见多态性与绝经前乳腺癌患者的肿瘤进展相关，因为与非携带者相比，携带变异受体的患者无病生存期较短。然而，hCG及其受体如何对乳腺癌发挥作用尚不清楚。一种可能性是这些效应通过卵巢中存在的促黄体生成素受体发生，从而影响类固醇激素的产生。另一种可能性是这些效应通过乳腺肿瘤细胞自身存在的促黄体生成素受体发生，因为一些研究在正常和肿瘤性乳腺组织以及乳腺癌细胞系中均检测到了该受体。为了研究促黄体生成素信号在乳腺癌中是否可能产生直接作用，我们使用具有宽动态范围的定量逆转录聚合酶链反应（qRT-PCR）测量了1551个乳腺肿瘤和42种不同人类乳腺癌细胞系中促黄体生成素受体mRNA的表达水平。此外，还研究了促黄体生成素受体表达与临床病理因素之间的关联。检测验证表明，我们的检测方法仍能检测到每个反应体积低至10个拷贝的促黄体生成素受体cDNA。我们发现，62%的乳腺肿瘤样本和42个乳腺癌细胞系中的41个未检测到促黄体生成素受体。对于其余样本，我们发现其表达水平非常低。尽管促黄体生成素受体的表达水平较低，但似乎与正常乳腺细胞、良好的肿瘤特征和低肿瘤比例相关。由于乳腺癌细胞中促黄体生成素受体的表达非常低，这几乎排除了直接信号作用的可能性。因此，我们得出结论，促黄体生成素受体对乳腺癌的信号作用很可能是通过卵巢的间接途径发生的。
