New development in intracrinology of breast carcinoma: Therapeutic horizons after aromatase inhibitors

Aromatase inhibitors have become the gold standard of endocrine therapy in postmenopausal patients with estrogen receptor-positive or estrogen-dependent breast carcinoma, replacing tamoxifen. However, it is true that there are some potential problems to be overcome or improved on regarding aromatase inhibitor treatment of breast cancer. This especially includes the presence of the estrogen receptor-positive patients who do not necessarily respond to aromatase inhibitors, may require other modes of endocrine therapy and develop resistance to aromatase inhibitor in their clinical course, and who may also need alternative modes of suppressing intratumoral estrogen signals or other intracellular signal pathways related to tumor progression or development. Intratumoral estrogen production from precursors present in circulation in an 'intracrine' manner is considered to play very important roles in the development and progression of estrogen receptor-positive breast cancer. The great majority of estrone in circulation is present as a sulfated form or estrone sulfate, and steroid sulfatase hydrolyzes circulating estrone sulfate to estrone in various human tissues in situ, which confers potent estrogenic actions. Estrone is subsequently reduced to 17β-estradiol by 172b-hydroxysteroid dehydrogenase type 1. Therefore, these two enzymes also play very important roles in intracrinology of estrogen in breast cancer in addition to intratumoral aromatase, and the potential inhibition of these two enzymes could lead to the development of a new mode of endocrine therapy based on intracrinology, which may overcome some of the problems above in aromatase inhibitor therapy. In this review, the potential advantages and pitfalls or problems associated with the inhibition of these two intratumoral enzymes in breast cancer patients will be discussed.