Epidemiological
studies provide strong evidence that estrogens contribute to the development of
de
novo breast cancerand to
their growth when established. Specifically, these studies demonstrate an
increased risk of breast cancer with early menarche, delayed first birth,
late menopause, high body mass
index, breast density, plasma estrogen
levels, and use of menopausal hormone
therapy (MHT) containing estrogen plus a progestogen. Paradoxically, estrogen therapy alone in the Women’s Health
Initiative (WHI) study reduced breast cancer
risk by 23% (HR 0.77, 95% CI 0.62-0.95)
at 13 years of follow-up
(7 years of therapy and 6 years without). The mechanisms for this
paradox are becoming better understood
and will be reviewed in the presentation.
Estrogens appear to cause de novo breast cancer by both
ERα-dependent and - independent
effects. ERα-dependent actions result in
an increase in the rate of cell
division and resulting mutations. By the
conversion to genotoxic metabolites, estrogen causes mutations in an ERα–independent
fashion. The ERα knock out /Wnt 1 transgenic
mouse model provides the most compelling evidence of both ER α-dependent and -independent (i.e genotoxic) effects. As
evidence of ERα-dependent effects, knock
out of ERα reduces the incidence of breast cancer. Supporting an
ERα-independent effect, reduction of estradiol by oophorectomy in ERα knock out animals reduces the
incidence of breast cancer and add back
of this sex steroid restores this
parameter. Blockade of any residual ERα or β activity with the “pure”
anti-estrogen fulvestrant did not alter these findings. Clinical studies also
support an ERα-independent mechanism as
oophorectomy reduces the incidence of ER negative breast cancer in women with BRCA1 mutations. Importantly, the BRCA1
mutation is associated with increased production of genotoxic metabolites in
women.
To understand
how estradiol paradoxically prevents breast cancer, we developed two models to describe the life history of
breast cancer and validated these in 7 population models. It takes an average of 16 years to proceed
from development of de novo cancer to reach the detection threshold of mammography
or MRI. At autopsy, 7% of normal women
ages 40-80 harbor occult tumors too small to be detected by imaging.
Accordingly, MHT effects in the WHI
largely related to occult, established
tumors. The average age of women receiving estrogen alone in the WHI was 63 and
these women had undergone a period of estrogen deprivation of 12 years on
average after menopause. Based on our data, the reduction of breast cancer with
estrogen alone in the WHO appears likely to have resulted from estradiol-induced apoptosis. As evidence, our in vitro model of long term
estradiol deprivation demonstrated that estradiol causes apoptosis via both
death receptor and mitochondrial pathways. A key regulatory factor is AMP-K
with its downstream pro-apoptotic effects on FOXO-3, FAS-l, GADD 45, and BIM.
In summary, estradiol
can cause de novo breast cancer through ERα-dependent and-
independent effects and cause cell death in established, occult
tumors in post–menopausal women receivi9ng estrogen alone many years after
onset of menopause.