Dr. Ron’s Research Review – November 28, 2012

This week’s research review focuses on estrogen and breast cancer.

The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence. (Shapiro, Farmer et al. 2011)

Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. It is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. (Suba 2012)

Curcumin delays development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors (Carroll, Benakanakere et al. 2010)

Dr. Ron


Abstracts

Curcumin delays development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors

            (Carroll, Benakanakere et al. 2010) Download

OBJECTIVE: Combined hormone therapy (HT) containing estrogen and progestin (medroxyprogesterone acetate [MPA]) leads to increased risk of breast cancer in postmenopausal women, compared with HT regimens containing estrogen alone or placebo. We previously reported that in animal models, progestins can accelerate the development of mammary tumors by increasing vascular endothelial growth factor (VEGF) levels. We furthermore showed that curcumin, an Indian spice derived from the turmeric root, specifically inhibits MPA-induced VEGF secretion from breast cancer cells in vitro. In the present study, we investigated whether curcumin inhibits 7,12-dimethylbenz[a]anthracene (DMBA)-induced, MPA-accelerated tumors in Sprague-Dawley rats. METHODS: On day 0, virgin female Sprague-Dawley rats (age, 55 d) were given DMBA (20 mg/rat). Sixty-day timed-release pellets containing 25 mg MPA were implanted into the rats on day 30. Curcumin was administered daily at a rate of 200 mg kg-1 day-1 from days 26 to 50, and animals were killed on day 52 (n = 15-19 per group). RESULTS: Treatment with curcumin delayed the first appearance of MPA-accelerated tumors by 7 days, decreased tumor incidence by the end of the experiment, and reduced tumor multiplicity in DMBA-induced MPA-accelerated tumors. Curcumin also prevented many of the gross histological changes seen in the MPA-treated mammary gland. Immunohistochemical analyses of mammary tumors showed that curcumin decreased MPA-induced VEGF induction in hyperplastic lesions, although it did not affect the levels of estrogen and progesterone receptors. CONCLUSIONS: We suggest that curcumin be tested as a dietary chemopreventive agent in women already exposed to MPA, in an effort to decrease or delay the risk of breast cancer associated with combined HT.

Hormone therapy and fatal breast cancer

         (Norman, Weber et al. 2010) Download

PURPOSE: Among unanswered questions is whether menopausal use of estrogen therapy (ET) or estrogen-plus-progestin therapy (CHT) increases risk of developing fatal breast cancer i.e., developing and dying of breast cancer. Using a population-based case-control design, we estimated incidence rate ratios of fatal breast cancer in postmenopausal hormone therapy (HT) users compared to non-users by type, duration, and recency of HT use. METHODS: HT use prior to breast cancer diagnosis in 278 women who died of breast cancer within 6 years of diagnosis (cases) was compared with use in 2224 controls never diagnosed with breast cancer using conditional logistic regression. Measures taken to address potential bias and confounding inherent in case-control studies included collecting and adjusting for detailed data on demographic and other factors potentially associated both with HT use and breast cancer. RESULTS: Fifty-six per cent of cases and 68% of controls reported HT use. Among current 3+ year HT users, odds ratios and 95% confidence intervals for death were 0.83 (0.50, 1.38) and 0.69 (0.44, 1.09), respectively, for exclusive use of CHT or of ET, and were 0.94 (0.59, 1.48) and 0.70 (0.45, 1.07) for any use of CHT or of ET regardless of other hormone use. CONCLUSION: Point estimates suggest no increased risk of fatal breast cancer with HT use, although 50% increases in risk in longer-term current CHT users cannot be ruled out.

Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen

            (Shapiro, Farmer et al. 2011) Download

BACKGROUND: Studies from the Women's Health Initiative have reported an increased risk of breast cancer in users of estrogen plus progestogen. Among users of estrogen alone an increased risk was not observed. OBJECTIVE: To evaluate the evidence for unopposed estrogen. METHODS: In a related article (Part 2) the authors apply generally accepted causal criteria to the findings for estrogen plus progestogen. Here (Part 3) the authors apply the criteria to the findings for unopposed estrogen, as reported in a clinical trial, and in combined data from the trial and an observational study. RESULTS: In the clinical trial, after 7.1 years of follow-up the relative risk (RR) of invasive breast cancer for women assigned to estrogen was 0.77 in an 'intention-to-treat' analysis (95% CI 0.59-1.01) and 0.67 (95% CI 0.47-0.97) in an 'as treated' analysis; after 10.7 years the risk reduction persisted. Time order was correctly specified; detection bias was minimal; in the 'as treated' analysis confounding was unlikely; duration-response and internal consistency could be evaluated only to a limited extent because of scanty data; the findings were discordant with increased risks observed in the Collaborative Reanalysis and the Million Women Study; biological plausibility could not be assessed. In the combined analysis, among women who had previously used estrogen soon after the menopause there was no clear evidence of either a reduction or an increase in the risk of breast cancer among women assigned to estrogen during the trial, or among women who were using estrogen in the observational study when follow-up commenced. The combined analysis did not satisfy the criteria of time order, bias, confounding, statistical stability and strength of association, duration-response, and internal consistency; biological plausibility could not be assessed. CONCLUSIONS: The evidence from the clinical trial suggests that unopposed estrogen does not increase the risk of breast cancer, and may even reduce it. The latter possibility, however, is based on statistically borderline evidence.


Circulatory Estrogen Level Protects Against Breast Cancer in Obese Women

            (Suba 2012) Download

Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer.


References

Carroll, C. E., I. Benakanakere, et al. (2010). "Curcumin delays development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors." Menopause 17(1): 178-84.

Norman, S. A., A. L. Weber, et al. (2010). "Hormone therapy and fatal breast cancer." Pharmacoepidemiol Drug Saf 19(5): 440-7.

Shapiro, S., R. D. Farmer, et al. (2011). "Does hormone replacement therapy cause breast cancer? An application of causal principles to three studies: part 3. The Women's Health Initiative: unopposed estrogen." J Fam Plann Reprod Health Care 37(4): 225-30.

Suba, Z. (2012). "Circulatory Estrogen Level Protects Against Breast Cancer in Obese Women." Recent Pat Anticancer Drug Discov.