Costantino Lucia, Catalano Maria G, Frairia Roberto, Carmazzi Carlo M, Barbero Maggiorino, Coluccia Claudio, Donadio Michela, Genta Franco, Drogo Mauro, Boccuzzi Giuseppe, Fortunati Nicoletta
Laboratory of Oncological Endocrinology, ASO San Giovanni Battista, Via Genova 3, Turin 10126, Italy.
Breast Cancer Res Treat. 2009 Apr;114(3):449-56. doi: 10.1007/s10549-008-0031-4. Epub 2008 Apr 25.
Sex Hormone-Binding Globulin, the specific carrier for sex steroids, regulates hormone bioavailable fraction and estrogen signaling system in breast cancer cells. A common single nucleotide polymorphism in the human SHBG gene results in an amino acid substitution (Asp327Asn), which introduces an additional N-glycosylation site, and is associated with reduced breast cancer risk in postmenopausal women. The frequency of this polymorphism was evaluated in a group of patients that developed breast cancer while taking hormonal replacement therapy (HRT) for menopause, an interesting model of estrogen exposure. The polymorphism frequency was significantly higher in women taking HRT that didn't develop any breast cancer than in breast cancer patients (P<0.05). To get insight into the underlying mechanisms, we compared the ability of recombinant wild type and variant (D327N) SHBG to influence estradiol effects in MCF-7 breast cancer cells. D327N SHBG was more effective than wild type protein in inhibiting estradiol-induced cell proliferation and anti-apoptosis. This depended on the fact that D327N SHBG binding to MCF-7 cells was significantly higher than that of wild type protein. As a consequence, D327N caused a larger induction of the second messenger cAMP and a deeper inhibition of the estradiol-induced Erk (1/2) phosphorylation. Our observations, demonstrating the increased efficiency of D327N SHBG in counteracting estradiol action and a significantly higher frequency of Asp327Asn polymorphism in women not developing breast cancer after estrogen exposure, first provide evidence for the mechanism of D327N SHBG protective action.
性激素结合球蛋白是性类固醇的特异性载体，可调节乳腺癌细胞中的激素生物可利用分数和雌激素信号系统。人类SHBG基因中一种常见的单核苷酸多态性导致氨基酸替换（Asp327Asn），这引入了一个额外的N-糖基化位点，并且与绝经后女性患乳腺癌风险降低相关。在一组因更年期接受激素替代疗法（HRT）而患乳腺癌的患者中评估了这种多态性的频率，这是一个雌激素暴露的有趣模型。未患任何乳腺癌的接受HRT的女性中该多态性频率显著高于乳腺癌患者（P<0.05）。为深入了解潜在机制，我们比较了重组野生型和变体（D327N）SHBG影响MCF-7乳腺癌细胞中雌二醇作用的能力。D327N SHBG在抑制雌二醇诱导的细胞增殖和抗凋亡方面比野生型蛋白更有效。这取决于D327N SHBG与MCF-7细胞的结合显著高于野生型蛋白这一事实。因此，D327N导致第二信使cAMP的诱导更大，并且对雌二醇诱导的Erk（1/2）磷酸化的抑制更深。我们的观察结果表明D327N SHBG在对抗雌二醇作用方面效率提高，并且在雌激素暴露后未患乳腺癌的女性中Asp327Asn多态性频率显著更高，首次为D327N SHBG的保护作用机制提供了证据。
