Suba Zsuzsanna
National Institute of Oncology, Budapest, Hungary.
Drug Des Devel Ther. 2014 Sep 11;8:1381-90. doi: 10.2147/DDDT.S70570. eCollection 2014.
Recognition of the two main pathologic mechanisms equally leading to breast cancer development may provide explanations for the apparently controversial results obtained by sexual hormone measurements in breast cancer cases. Either insulin resistance or estrogen receptor (ER) defect is the initiator of pathologic processes and both of them may lead to breast cancer development. Primary insulin resistance induces hyperandrogenism and estrogen deficiency, but during these ongoing pathologic processes, ER defect also develops. Conversely, when estrogen resistance is the onset of hormonal and metabolic disturbances, initial counteraction is hyperestrogenism. Compensatory mechanisms improve the damaged reactivity of ERs; however, their failure leads to secondary insulin resistance. The final stage of both pathologic pathways is the breakdown of estrogen surveillance, leading to breast cancer development. Among premenopausal breast cancer cases, insulin resistance is the preponderant initiator of alterations with hyperandrogenism, which is reflected by the majority of studies suggesting a causal role of hyperandrogenism in breast cancer development. In the majority of postmenopausal cases, tumor development may also be initiated by insulin resistance, while hyperandrogenism is typically coupled with elevated estrogen levels within the low postmenopausal hormone range. This mild hyperestrogenism is the remnant of reactive estrogen synthesis against refractory ERs that were successfully counteracted at a younger age. When refractoriness of ERs is the initiator of pathologic processes, reactively increased estrogen levels may be found in both young and older breast cancer cases, while they may exhibit clinical symptoms of estrogen deficiency. Studies justifying a causal correlation between hyperestrogenism and tumor development compile such breast cancer cases. In conclusion, the quantitative evaluation of ER refractoriness in breast cancer cases has great importance, since the stronger the estrogen resistance, the higher the promising dose of estrogen therapy.
认识到两种同样会导致乳腺癌发生的主要病理机制，或许能解释在乳腺癌病例中通过性激素测量所得到的明显相互矛盾的结果。胰岛素抵抗或雌激素受体（ER）缺陷均是病理过程的起始因素，二者均可导致乳腺癌的发生。原发性胰岛素抵抗会引发高雄激素血症和雌激素缺乏，但在这些持续的病理过程中，ER缺陷也会出现。相反，当雌激素抵抗是激素和代谢紊乱的起始因素时，最初的反应是雌激素过多。代偿机制会改善受损的ER反应性；然而，若代偿机制失效则会导致继发性胰岛素抵抗。这两种病理途径的最终阶段都是雌激素监测功能的崩溃，从而导致乳腺癌的发生。在绝经前乳腺癌病例中，胰岛素抵抗是伴有高雄激素血症的改变的主要起始因素，这一点在大多数表明高雄激素血症在乳腺癌发生中起因果作用的研究中都有所体现。在大多数绝经后病例中，肿瘤的发生也可能由胰岛素抵抗引发，而高雄激素血症通常与绝经后低激素水平范围内升高的雌激素水平相关。这种轻度的雌激素过多是针对在年轻时已成功对抗的难治性ER的反应性雌激素合成的残余现象。当ER的难治性是病理过程的起始因素时，在年轻和老年乳腺癌病例中都可能发现反应性升高的雌激素水平，而这些病例可能会表现出雌激素缺乏的临床症状。证明雌激素过多与肿瘤发生之间存在因果关系的研究纳入了此类乳腺癌病例。总之，对乳腺癌病例中ER难治性进行定量评估非常重要，因为雌激素抵抗越强，雌激素治疗的有效剂量就越高。
