Year: 2016
Type: conference-abstract
Abstract: 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 ERa-dependent and -independent effects.ERa-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 ERa-independent fashion.The ERa knock out /Wnt 1 transgenic mouse model provides the most compelling evidence of both ER a-dependent and -independent (i.e genotoxic) effects.As evidence of ERa-dependent effects, knock out of ERa reduces the incidence of breast cancer.Supporting an ERa-independent effect, reduction of estradiol by oophorectomy in ERa knock out animals reduces the incidence of breast cancer and add back of this sex steroid restores this parameter.Blockade of any residual ERa or b activity with the "pure" anti-estrogen fulvestrant did not alter these findings.Clinical studies also support an ERa-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 proapoptotic effects on FOXO-3, FAS-l, GADD 45, and BIM.In summary, estradiol can cause de novo breast cancer through ERadependent and-independent effects and cause cell death in established, occult tumors in post-menopausal women receiving estrogen alone many years after onset of menopause. 20The vitamin D receptor (VDR) is expressed in skeletal muscle of male mice and modulates 25-hydroxyvitamin D (25OHD) uptake in myofibers Christian
Source: Clinical Endocrinology
DOI: 10.1111/cen.13010
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2428408080