Sex
steroids play an important role in the development and differentiation in several tissues. Biologically active
hormones that are locally converted in endocrine organs in the tissue where they exert their effects without release into extracellular space is a field of endocrinology that has been called intracrinology. In pre-menopausal women the ovary is the main source of
estrogens, but in post-menopausal women the
estrogen production as main site of synthesis moves to peripheral tissues and almost all of the sex
steroids are synthesised from precursors of adrenal origin. In
breast cancer 60-80% of the
tumors express high levels of oestrogen receptor (ER) alpha which gives
estrogen a proliferative effect.
Breast tumors tend to have a higher intratumoral
estrogen concentration than normal breast tissue and plasma, and in situ synthesis and the metabolism of
estrogens is believed to be of great importance for the development and progression of the disease. The activity of
estrogen metabolizing
enzymes in breast are mainly
aromatase,
estrone sulfatases and 17HSD
enzymes.
17HSD1 and 17HSD2 are the family members known to be of main importance in
breast cancer. High expression of
17HSD1 has been associated to poor prognosis in
breast cancer and late relapse among patients with ER-positive
tumors. One of the mechanisms behind high
17HSD1 expression is gene amplification. Low or absent expression of 17HSD2 is associated to decreased survival in ER-positive
breast cancer. 17HSD14 is one of the latest discovered 17HSD
enzymes, transfection of 17HSD14 in human
breast cancer cells significantly decreased the levels of
estradiol in the culture medium. Low expression of 17HSD14
mRNA expression in
breast cancer was correlated to decreased survival. The understanding of intratumoral synthesis of sex
steroids in
breast cancer is crucial to understand the disease both in pre- and post-menopausal women. Further studies are desirable to state the direct role of these
enzymes in
breast cancer and which patients that may benefit from new therapeutic strategies targeting 17HSD
enzymes. The new inhibitors targeting
17HSD1 have shown promising results in pre-clinical studies to have clinical potential in the future.