Diverse pathomechanisms leading to the breakdown of cellular estrogen surveillance and breast cancer development: new therapeutic strategies

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.