The oestrogen paradox: an hypothesis
© BioMed Central Ltd 2007
Published: 20 December 2007
Short-term oestrogen use and breast cancer risk
The initial publication of the Women's Health Initiative (WHI)  reported a 23% decrease in invasive breast cancer incidence in patients taking oestrogen alone compared with placebo, a finding which narrowly fell short of statistical significance (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.59 to 1.01). A recent exploratory analysis of updated data from this study examined subgroups to determine whether oestrogens might reduce the incidence of breast cancer significantly in women falling into certain categories . Notably, this analysis reported a statistically significant 33% reduction in invasive breast cancer incidence in patients who strictly adhered to their oestrogen therapy (HR 0.67, 95% CI 0.47 to 0.97). In addition, a 31% lower incidence of localized breast cancer (HR 0.69, 95% CI 0.51 to 0.95) and a 29% reduction in ductal cancers (HR 0.71, 95% CI 0.52 to 0.99) were reported in oestrogen users. The decreases in breast cancer risk were limited to women who had not previously used MHT . In a concurrent report from the
Nurses Health Study , a significant 26% decrease in risk for breast cancer was observed in obese women, and a nonsignificant 10% decrease in all study participants, taking oestrogen alone for 5 to 9 years. Other observational studies reported a reduction in risk with oestrogen alone but of lesser magnitude and not statistically significant. For example, Schairer and colleagues  reported a 7% reduction in breast cancer risk at 6 years in women receiving oestrogen alone, and Lyytinen and coworkers  identified a similar 7% reduction. These combined results, although not conclusive, are highly suggestive of a beneficial effect of oestrogen in reducing breast cancer risk. However, this conclusion must be considered provisional until rigorous confirmation in additional studies is reported.
Long-term oestrogen use and breast cancer risk
What are the data regarding use of oestrogen alone for more than 20 years? The Nurses Health Study  also evaluated women using oestrogen alone for more than 20 years and found a statistically significant 41% increase in breast cancer risk in women 50 years of age or older, and a 77% increase in the subset of lean women. Earlier studies by Magnusson  and Schairer  and their colleagues also identified significantly increased breast cancer risks in women taking oestrogen alone for more than 10 years (odds ratio 2.7) and 16 years (relative risk 1.6), respectively. The Million Women Study  also reported a linear increase in breast cancer risk over time in women receiving MHT with oestrogen alone over a period of 10 years. In contrast to the other studies reported, however, the Million Women Study found a nonsignificant increased risk for breast cancer, even in women receiving this therapy for less than 5 years.
High-dose oestrogens as breast cancer treatment
A second component of the oestrogen paradox is that women with hormone-dependent breast cancer respond to high-dose oestrogens with objective tumour regressions. This form of therapy was the mainstay of hormonal treatment of breast cancer from the late 1940s until the early 1980s [7–9]. When compared in randomized trials with tamoxifen, high-dose oestrogens were equally efficacious  and in one study they were associated with significantly enhanced survival  compared with an anti-oestrogen. Extensive studies demonstrated that only specific subgroups of women respond to high-dose oestrogen [9, 12]. Premenopausal women and those less than 1 year postmenopausal do not respond at all. Women who had undergone menopause many years earlier frequently experienced objective tumour regressions; the longer the duration of the period after cessation of menses, the greater the response rate. Only oestrogen receptor (ER)-positive tumours regress in women receiving high-dose oestrogens .
Possible mechanisms to explain the oestrogen paradox
Occult breast cancers found at autopsy
5% DCIS and 1% IBC
Occult pre-existing breast cancers in women
Over the past three decades at least eight studies have assessed the frequency of occult malignant disease, primarily ductal carcinoma in situ (DCIS), found at autopsy in women with no history of breast cancer  (Table 1). The frequency of occult DCIS varied considerably among these studies (range 0% to 15%), most likely reflecting methodological differences. Variation aside, approximately 5% of the 1,052 combined cases from these studies included occult DCIS and 1% occult invasive breast cancers . Based on these findings, it is reasonable to assume that 5% to 10% of the women entering the WHI and Nurse's Health Study had occult breast cancer when they were initially enrolled.
Evidence for oestradiol-induced apoptosis
Recent in vitro studies from our laboratory showed that hormone-dependent breast cancer cells deprived of oestrogen in the long term undergo adaptive changes that cause oestrogen to paradoxically stimulate apoptosis [13–15] (Figure 2a). Whereas wild-type MCF7 cells respond to oestradiol with a reduction in apoptosis, those deprived of oestrogen in the long term exhibit an increase in programmed cell death. Similarly, Jordan and collaborators [16–21] demonstrated that long-term tamoxifen exposure also results in adaptation and development of oestrogen-induced apoptosis. Apoptotic mechanisms in adapted cells involve upregulation of death receptor as well as mitochondrial pathways. Specific molecular events include activation of the Fas death receptor/Fas ligand complex, the release of cytochrome C from the mitochondria, alterations in Bcl-2, and downregulation of the anti-apoptotic factor nuclear factor-κ [14, 15, 18].
Long-term oestradiol deprivation in the Women's Health Initiative and the Nurse's Health Study
At the time of enrolment, participants in the WHI trial were 63 years old on average and menopausal for more than 10 years . Plasma oestradiol levels fall precipitously at menopause from 50 to 600 pg/ml to levels of 5 to 10 pg/ml. Even though breast tissue levels might not precisely reflect plasma concentrations, one would still expect substantial reduction in breast tissue levels and adaptation to this reduction. If our hypothesis were correct, then exposure to oestrogen therapy as MHT would induce apoptosis and shrink or even eradicate the occult tumours, which would reduce the detection of a cancer by mammography or palpation over the next several years. This scenario could explain the reduction in breast cancers diagnosed in the WHI and Nurses Health Study in women receiving oestrogen alone as MHT for 5 to 9 years [2, 4]. This hypothesis would also explain why women who had received MHT before entering the WHI study did not experience a reduction in breast cancer risk .
Long-term exposure to oestradiol
A variety of data are congruent with our 'oestrogen paradox' hypothesis; however, additional confirmatory studies are needed to prove this contention. Specifically needed are more comprehensive autopsy studies to determine precisely the magnitude of the reservoir of occult breast cancers and their precursor lesions. The ability of highly sensitive imaging strategies, such as digital mammography and magnetic resonance imaging, should be evaluated for their abilities to detect occult breast cancers in women initiating MHT. Direct demonstration of oestrogen-induced apoptosis in occult breast cancers in women will also be critical.
This article has been published as part of Breast Cancer Research Volume 9 Supplement 2, 2007: Controversies in Breast Cancer. The full contents of the supplement are available online at http://breast-cancer-research.com/supplements/9/S2.
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