Estrogens provide the major hormonal support for endocrine-dependent
human mammary neoplasms. In postmenopausal women, the extraglandular aromatization of the adrenal prehormone,
androstenedione to
estrone is the major pathway for
estrogen biosynthesis.
Estrone can then be converted into
estradiol or into an inactive conjugate,
estrone sulfate. Recent data suggest that the
estrogens may also be synthesized in situ by human
breast tumors, either from
androstenedione via
aromatase, or from
estrone sulfate via the
enzyme,
sulfatase. Our
enzyme kinetic studies support the predominance of the
sulfatase pathway for in situ
estrogen biosynthesis. The ability of
estrone sulfate to stimulate colony formation of the
nitrosomethylurea-induced rat mammary
tumor in the clonogenic assay, suggests that this in situ pathway has
biologic relevance.
Aromatase inhibitors can be used to suppress the levels of circulating
estrone,
estrone sulfate, and
estradiol in postmenopausal women.
Aminoglutethimide, the major inhibitor currently used clinically, acts in a competitive fashion and blocks
cholesterol side chain cleavage and
11 beta-hydroxylase as well as
aromatase. Clinical studies indicate that the combination of
aminoglutethimide plus replacement
glucocorticoid causes
breast tumor regression with the same frequency and for the same duration as surgical ablative
therapies such as
adrenalectomy or
hypophysectomy.
Aminoglutethimide also induces a similar rate of
tumor regression as achieved with the
antiestrogen,
tamoxifen. However, because
tamoxifen is associated with fewer side effects, this
antiestrogen is to be preferred over use of
aminoglutethimide as first-line hormonal treatment for women with
breast cancer. Several specific suicide inhibitors of
aminoglutethimide such as 4-hydroxy-androstenedione are being developed and have proven effective in early clinical trials with
breast cancer patients. Further development of active
aromatase inhibitors should allow precise control of
estradiol levels in women with
breast cancer. This ability to perform an '
estrogen clamp' may allow new strategies to be developed in which
hormone depletion followed by repletion can produce a synchronization of
tumor cell
DNA synthesis. If achievable, such manipulations may allow potentiation of the effects of cytotoxic
chemotherapy. This latter concept is currently being rigorously tested in basic and in clinical investigative studies.