More than two-thirds of breast
cancers occur in post-menopausal women, and depend on the
estrogens for their proliferation and survival. For the treatment of
estrogen-dependent breast
cancers, two major treatment options are now available. One is
selective estrogen receptor modulator (
SERM) such as
Tamoxifen and another is
aromatase inhibitor such as
Anastrozole,
Letrozole and
Exemestane, which reduce local in situ formation of
estrogens. Although these
therapies are clinically active for advanced and early breast
cancers, de novo and/or acquired resistance to
SERM and/or
aromatase inhibitors are also clinical problem. Recent studies suggest that local formation of
estrogens in the
breast tumors is more important than circulating
estrogen in plasma for the growth and survival of
estrogen-dependent
breast cancer in post-menopausal women. The rationale for the importance of local formation of
estrogens is based on the following evidences.
Estradiol (E2) levels in
breast tumors are equivalent to those of pre-menopausal patients, although plasma E2 levels are 50-fold lower after menopause. E2 concentrations in
breast tumors of post-menopausal women are 10-40 times higher than serum level. Biosynthesis of
estrogens in
breast tumors tissues occurs via two major different routes, one is
aromatase pathway and another is
steroid-sulfatase (STS) pathway. Whereas many studies has been reported about
aromatase inhibitor and its clinical trial results in
breast cancer patients, limited information are available regarding to other
estrogen regulating
enzymes including STS, its role in
breast tumors and STS inhibitors. STS is the
enzyme that hydrolyses
estrone 3-sulfate (E1S) and
dehydroepiandrosterone-sulfate (
DHEA-S) to their active un-sulfoconjugated forms, thereby stimulating the growth and survival of
estrogen-dependent
breast tumors. It has been well known that E1S level are much higher than E2 level both in plasma and
tumor of post-menopausal patients. Recent reports show that more than 80% of
breast tumors are stained with anti-STS antibody and the expression of STS is an independent prognostic factor in
breast cancer. Taking these findings into consideration, local formation of
estrogens could be partially synthesized from large amount of E1S by STS, which exist in
breast cancer. On the other hand,
aromatase localizes in stroma and adipocyte surrounding
breast cancer. Furthermore, since
estrogen formation from E1S and
DHEA-S (STS pathway) cannot be blocked by
aromatase inhibitors, STS is thought to be a new molecular target for the treatment of
estrogen-dependent
tumor post-
SERM and/or
aromatase inhibitors. In this symposium, these recent rationale for the importance of STS in post-menopausal
breast cancer patients is reviewed as well as STS inhibitor.