Estrogen effects on the mammary gland in early and late life and breast cancer risk

A woman has an increased risk of breast cancer if her lifelong estrogen exposure is increased due to an early menarche, a late menopause, and/or an absence of childbearing. For decades, it was presumed that the number of years of exposure drove the increased risk, however, recent epidemiological data have shown that early life exposure (young menarche) has a more significant effect on cancer risk than late menopause. Thus, rather than the overall exposure it seems that the timing of hormone exposure plays a major role in defining breast cancer risk. In support of this, it is also known that aberrant hormonal exposure prior to puberty can also increase breast cancer risk, yet the elevated estrogen levels during pregnancy decrease breast cancer risk. This suggests that the effects of estrogen on the mammary gland/breast are age-dependent. In this review article, we will discuss the existing epidemiological data linking hormone exposure and estrogen receptor-positive breast cancer risk including menarche, menopause, parity, and aberrant environmental hormone exposure. We will discuss the predominantly rodent generated experimental data that confirm the association with hormone exposure and breast cancer risk, confirming its use as a model system. We will review the work that has been done attempting to define the direct effects of estrogen on the breast, which are beginning to reveal the mechanism of increased cancer risk. We will then conclude with our views on the most pertinent questions to be addressed experimentally in order to explore the relationship between age, estrogen exposure, and breast cancer risk. Breast cancer remains one of the most prevalent diseases in the western world, with one in eight women predicted to be affected by breast cancer in their lifetime. Improvements in detection, anti-estrogen therapies, and cytotoxic chemotherapy have led to increased survival rates, from 72% in 1980s to 89% in 2010. Despite this, the incidence of breast cancer has increased over the same period (1, 2). This year in Australia, 15,930 women are predicted to be diagnosed with breast cancer and this figure is expected to rise to 17,210 women by 2020. Similar increases in incidence have been reported in America, the United Kingdom, and China (3-5). Estrogen receptor (ER)-positive breast cancers are the only subtype that are increasing (6-9) and as they make up 75-80% of all breast cancer cases this may explain the increase in breast cancer incidence overall. It has been postulated that the rising incidence of ER+ breast cancer is driven by hormonal risk factors such as low and/or late parity, early menarche, late menopause, as well as the use of combined oral contraceptive (OCP) pill and postmenopausal hormone replacement therapy (HRT) (10-13) rather than determinants such as BMI and BRCA1/2 status. In this review we will discuss the epidemiological data and experimental models used to investigate the effects of these different hormonal factors on ER+ breast cancer risk.