Why does oestrogen-only hormone therapy have such a small impact on breast cancer risk? A hypothesis

There seems to be irrefutable evidence that oestrogen is involved in the pathogenesis of breast cancer. The disease mostly affects women and the epidemiology of breast cancer relates to reproductive markers such as pregnancy, age at menarche and age of menopause. Most breast cancers elaborate oestrogen receptors (ER) and in such cases endocrine therapies such as tamoxifen and aromatase-inhibitors (AIs) are effective adjuvant treatments. However, high-quality randomised controlled trials (RCTs) (such as the WHI study) have shown that oestrogen-only hormone therapy (ET) does not increase breast cancer risk at all. This would seem to be a remarkable paradox. There appears to be at least two reasons for this apparent contradiction. First, it has been known for two decades that the breast itself produces oestrogens locally and the microenvironment around a breast cancer is more important that the impact of systemic-oestrogens. Second, breast cancer stem cells (breast CSC) have been identified and it seems likely that these long-lived, multipotential cells are responsible for the genesis of many breast cancers, as well as their malignant behaviour. Breast CSC usually do not contain sex-hormone receptors, but their offspring often elaborate ER and progesterone receptor (PR). Thus, it appears unlikely that oestrogen per se initiates breast cancer, but rather might stimulate an existing tumour.