Current knowledge of the multifunctional 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1)

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) was the first identified member of the 17β-HSD family, with its gene cloned in the late 1940s.
• The human 17β-HSD1 is the first characterized human steroid-converting enzyme, extensively studied for its structure and function.
• This enzyme is expressed in human placenta, ovary, endometrium, and breast tissues.

Purpose of the Study:

• To investigate the role of 17β-HSD1 in estrogen-dependent diseases.
• To explore the dual function of 17β-HSD1 in estrogen activation and androgen inactivation.
• To evaluate the potential of 17β-HSD1 inhibitors as therapeutic agents.

Main Methods:

• Structural and functional studies of human 17β-HSD1.
• Molecular and cell-level analyses in breast cancer models.
• Evaluation of 17β-HSD1 overexpression in clinical samples.
• Assessment of xenograft tumor response to 17β-HSD1 inhibition.

Main Results:

• 17β-HSD1 significantly contributes to estrogen activation, implicated in breast cancer, endometriosis, and lung carcinomas.
• The enzyme's dual role in estrogen activation and androgen inactivation promotes cancer cell proliferation.
• Clinical samples show overexpression of 17β-HSD1 in breast cancer.
• Inhibition of 17β-HSD1 resulted in xenograft tumor shrinkage.

Conclusions:

• 17β-HSD1 is a key enzyme in estrogen-dependent pathologies.
• Current inhibitors face challenges due to estrogenic activity, necessitating novel approaches.
• Development of non-steroid, non-estrogenic inhibitors for 17β-HSD1 presents a promising therapeutic avenue.