Abstract
Estrogen overproduction is closely associated with the development of estrogen receptor-positive breast cancer. Aromatase, encoded by the cytochrome P450 19 (CYP19) gene, regulates estrogen biosynthesis. This study aimed to identify active flavones that inhibit CYP19 expression and to explore the underlying mechanisms. CYP19 expression was evaluated using reverse transcription PCR, quantitative real-time PCR, and immunoblot analysis. The role of transcription factor early growth response gene 1 (EGR-1) in CYP19 expression was assessed using the short-hairpin RNA (shRNA)-mediated knockdown of EGR-1 expression in estrogen receptor-positive MCF-7 breast cancer cells. We screened 39 flavonoids containing 26 flavones and 13 flavanones using the EGR1 promoter reporter activity assay and observed that chrysoeriol exerted the highest inhibitory activity on tumor necrosis factor alpha (TNFα)-induced EGR-1 expression. We further characterized and demonstrated that chrysoeriol inhibits TNFα-induced CYP19 expression through inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated EGR-1 expression. Chrysoeriol may be beneficial as a dietary supplement for the prevention of estrogen receptor-positive breast cancer, or as a chemotherapeutic adjuvant in the treatment of this condition.
Highlights
Introduction90% of all breast cancers are sensitive to female hormones, such as estrogen and progesterone, while two-thirds of postmenopausal breast cancers are estrogen-dependent [1]
Breast cancer is the most common form of cancer diagnosed in women worldwide
Aberrant expression of cytochrome P450 19 gene (CYP19) aromatase is not regulated by the proliferation of tumor cells or clinical course; instead, it occurs as a result of interaction between tumor cells and stromal cells [53,54]
Summary
90% of all breast cancers are sensitive to female hormones, such as estrogen and progesterone, while two-thirds of postmenopausal breast cancers are estrogen-dependent [1]. Abnormal local overproduction of estrogen in breast tissues is implicated in breast cancer pathogenesis. There is a significant correlation between tumor incidence and aromatase activity in breast tissue [3], and aberrant aromatase expression is closely associated with breast cancer development [1], suggesting the etiological role of estrogen in breast cancer incidence. As the expression of the estrogen receptor (ER) is considerably high in breast tumors, targeting the ER or estrogen deprivation has been recognized as a potential strategy for the treatment or prevention of breast cancer. Inhibition of estrogen synthesis by aromatase inhibitors or ER antagonists prevents breast cancer development in postmenopausal women [4,5]
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