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Risk Factors Associated With the Development of Breast Cancer
Source publication
From 2002 to 2008, reports from the Women's Health Initiative (WHI) claimed that hormone replacement therapy (HRT) significantly increased the risks of breast cancer development, cardiac events, Alzheimer disease, and stroke. These claims alarmed the public and health professionals alike, causing an almost immediate and sharp decline in the numbers...
Contexts in source publication
Context 1
... of the studies of HRT and risk of disease, especially breast cancer, have produced statistically modest or borderline results that have been made to look more impressive than they actually are by reporting them as relative risks. Consider Table 1, which lists the reported increases in relative risks associated not only with HRT 25,34 and ERT 35 but also with birth weight, 36 fish intake, 37 eating 1 additional serving of French fries per week during pre- school years, 38 eating grapefruit, 39 working on a night shift, 40,41 working as an airline flight attendant in 2 different airlines, [42][43][44] suffering from severe caloric restriction during the 1944 -1945 Dutch famine, 45 taking antibiotics, 46 and the use of electric blankets by African-American women. 47 You can see at a glance how weak these associations are; to put them in perspective, we included the results for a real finding-smoking and lung cancer-at the bottom of the table. ...
Context 2
... further their case, some investigators have turned to retrospective analysis. Several of the "significant" associations in Table 1 were a result of data mining: the use of antibiotics increases relative risk, but not among women using tetracycline or macrolide for acne or rosacea 46 (apparently breast cancer needs to know why a woman is taking an antibiotic); the increased risk of surviving the Dutch famine occurs only among women who were between 2 and 9 at the time 45 ; and, in the most unintentionally funny result, the breast cancer risk associated with using electric blankets increased among African American women who used the blankets for more than 10 years-but only if those who used them for more than 6 months per year were excluded from analysis. 47 Table 2 includes some good examples of data mining too, such as a 2000 study that found a 40% increased risk of breast cancer associated with HRT. ...
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High mammographic density is associated with an increased risk of breast cancer, and of all known breast cancer risk factors has the greatest attributable fraction. Mammographic density is estimated to account for 16% of all breast cancers, but can be altered by endogenous and exogenous hormonal factors, and generally declines with age. Confounding...
Citations
... Synthetic estrogen drugs include ethinylestradiol, ethinylether, and estradiol valerate, which have long-lasting effects. While estrogen replacement therapy is effective in reducing the risk of osteoporosis during menopause, long-term use of estrogen has been associated with increased risk of serious diseases [135] such as endometrial cancer, breast cancer, venous thrombosis, and stroke [136]. Combining this with progesterone, as in EPT, can alleviate some of these risks, particularly for endometrial cancers. ...
Osteoporotic fractures lead to increased disability and mortality in the elderly population. With the rapid increase in the aging population around the globe, more effective treatments for osteoporosis and osteoporotic fractures are urgently required. The underlying molecular mechanisms of osteoporosis are believed to be due to the increased activity of osteoclasts, decreased activity of osteoblasts, or both, which leads to an imbalance in the bone remodeling process with accelerated bone resorption and attenuated bone formation. Currently, the available clinical treatments for osteoporosis have mostly focused on factors influencing bone remodeling; however, they have their own limitations and side effects. Recently, cytokine immunotherapy, gene therapy, and stem cell therapy have become new approaches for the treatment of various diseases. This article reviews the latest research on bone remodeling mechanisms, as well as how this underpins current and potential novel treatments for osteoporosis.
... Therefore, they play a crucial role in recognizing menopausal symptoms in the workplace. The misinterpretation of the WHI (Women's Health Initiative) Study [22] has led to an irrational fear of treating women with menopausal symptoms by hormone replacement therapy, both by the general population and medical professionals. This has not only led to a drastic fall in the number of women using HST [23], but also to a paucity of menopause education in medical school curricula [24,25]. ...
Objective
To explore the attitudes, confidence and social norm of Dutch occupational physicians (OPs) regarding menopause in a work context.
Study design
A nationwide cross-sectional exploratory design. An invitation to participate in an online survey was sent to all OPs registered at the Dutch occupational physicians’ society (n = 1663). This survey collected data about attitudes, confidence, social norm and current practice of OPs regarding menopause and work. Descriptive statistics and post hoc logistic multivariate analyses were used to evaluate the data. Main outcome measures: Attitudes, confidence and social norms in relation to menopause and work.
Results
Data from 267 OPs were analysed. Most OPs do recognize a role for menopause in presenteeism and sickness absence. However, 48% stated that women with bothersome menopausal symptoms are ‘not sick’ and ‘just experiencing symptoms of a normal physiological process’. Over 56% of OPs find it difficult to assess the relationship between menopausal symptoms and work ability, and 63% to report menopause as a diagnosis in the context of a sick leave certification. Over 56% of OPs acknowledge that talking about menopause in the workplace is a taboo. A positive attitude towards menopause (OR 1.11, 95% CI 1.02-1.20) and greater confidence (OR 1.22, 95% CI 1.14-1.31) were associated with significantly higher levels of diagnosing menopause in sick leave certification.
Conclusions
Dutch OPs generally have a positive attitude towards menopause, but perceive a lack of knowledge and a taboo culture around menopause in a work context. They indicate a need for education and a guideline on menopause and work.
... Therefore, they play a crucial role in recognizing menopausal symptoms in the workplace. The misinterpretation of the WHI (Women's Health Initiative) Study [22] has led to an irrational fear of treating women with menopausal symptoms by hormone replacement therapy, both by the general population and medical professionals. This has not only led to a drastic fall in the number of women using HST [23], but also to a paucity of menopause education in medical school curricula [24,25]. ...
Objective
In this study we aimed to pilot test the hypothesis that in women who are severely bothered by their menopausal complaints, improvement of menopausal symptoms is associated with an improvement in self-perceived work ability.
Study design
This retrospective cohort study assessed the work ability of first-time attendees (n = 31) of a menopause clinic at baseline (T0) and 3–9 months follow-up (T1). All patients received care as usual according to local protocol, no interventions were applied by the researchers. Self-reported questionnaire data assessing work ability (Work Ability Index; WAI) and menopausal symptoms (Greene Climacteric Scale; GCS) were used.
Main outcome measures
Multiple linear regression was used in an exploratory analysis to examine the relationship between change in WAI score (ΔWAI) and change in menopausal symptoms (ΔGCS), after adjustment for potential confounders. Additional exploratory univariate linear regression analyses were performed to assess the associations of change in WAI score with change in the different GCS domains and with type of treatment.
Results
Twenty-seven out of 31 women reported improvement in work ability at follow-up (T1) (M = 30.73, SD = 6.42 respectively, M = 34.86, SD = 5.98). All women reported to be less bothered by their menopausal symptoms at T1 (M = 26.57, SD = 8.69 respectively, M = 14.73, SD = 6.36). Multivariate linear regression demonstrated a significant association between the WAI and GCS change scores after correction for confounders (beta ΔGCS = 0.283, p = 0.014). After additional adjustment for WAI at baseline, this association was no longer significant (beta ΔGCS = 0.172, p = 0.164). Change in GCS depression domain (ΔGCS depression) was significantly associated with ΔWAI, although after correction for WAI at baseline the effect of ΔGCS depression was no longer significant (beta = 0.855, p = 0.113). The WAI and GCS change scores were highly correlated, as a result their coefficients were not statistically significant separately.
Conclusions
Treatment aimed at alleviating menopausal symptoms in symptomatic women could lead to improvement of menopausal symptoms along with improvement in work ability. Improvement of depressive symptoms seem particularly important for this outcome.
... Many studies have explained the ovariectomy-induced cardiac apoptosis through constrain mitochondrial apoptotic pathways in rat models (5). The results of clinical trials have shown that hormone replacement therapy (HRT) such as estrogen therapy raised serious concerns about the use of this treatment in menopausal and postmenopausal women (6) including the increased risks of breast cancer (7), vascular disease and hypertension (8). Some studies have been performed to examine other procedures that have estrogenic effects on the cardiovascular system (9). ...
Objectives:
The beneficial and more potent role of exercise to prevent heart apoptosis in ovariectomized rats has been known. The aim of this study was to examine the effects of swimming training on cardiac expression of Bcl-2, and Mir-133 levels and glycogen changes in the myocyte.
Materials and methods:
Forty animals were separated into four groups as control, sham, ovariectomy (OVX) and ovariectomized group with 8 weeks swimming training (OVX.E). Training effects were evaluated by measuring lipid profiles, Bcl-2 and Mir-133 expression levels in the cardiac tissue. Grafts were analyzed by reverse transcription-polymerase chain reaction for Bcl-2 mRNA and Mir-133 and by Western blot for Bcl-2 protein.
Results:
Ovariectomy down-regulated Bcl-2 and Mir-133 expression levels in the cardiac tissue, and swimming training up-regulated their expression significantly (P<0.05).
Conclusion:
Our results showed that regular exercise as a physical replacement therapy could prevent and improve the effects of estrogen deficiency in the cardia.
... This is a small cohort and our observations need to be validated in a larger study. Nevertheless, given the benefits conferred by ET on bone density, cognitive function and cardiovascular disease [68], the studies presented here emphasize the need for additional studies to elucidate the optimum route of E2 delivery and in particular the effect of oral (subject to hepatic first pass effects) versus transdermal (including vaginal) administration. They also highlight the need to identify a target blood level of E2 needed to enhance immune response to vaccination in post-menopausal women and achieve a better understanding of the impact of acute and chronic exposure to estrogen on immunity. ...
It is widely recognized that changes in levels of ovarian steroids modulate severity of autoimmune disease and immune function in young adult women. These observations suggest that the loss of ovarian steroids associated with menopause could affect the age-related decline in immune function, known as immune senescence. Therefore, in this study, we determined the impact of menopause and estrogen therapy (ET) on lymphocyte subset frequency as well as the immune response to seasonal influenza vaccine in three different groups: 1) young adult women (regular menstrual cycles, not on hormonal contraception); 2) post-menopausal (at least 2 years) women who are not receiving any form of hormone therapy (HT) and 3) post-menopausal hysterectomized women receiving ET. Although the numbers of circulating CD4 and CD20 B cells were reduced in the post-menopausal group receiving ET, we also detected a better preservation of naïve B cells, decreased CD4 T cell inflammatory cytokine production, and slightly lower circulating levels of the pro-inflammatory cytokine IL-6. Following vaccination, young adult women generated more robust antibody and T cell responses than both post-menopausal groups. Despite similar vaccine responses between the two post-menopausal groups, we observed a direct correlation between plasma 17β estradiol (E2) levels and fold increase in IgG titers within the ET group. These findings suggest that ET affects immune homeostasis and that higher plasma E2 levels may enhance humoral responses in post-menopausal women.
... In the 1970's progesterone was added to regimens when a link was made between unopposed estrogen treatment and endometrial cancer (Smith, Prentice et al. 1975; Ziel and Finkle 1975). In the 1980's estrogen began to be prescribed as a prophylactic against osteoporosis when it was shown to reduce fractures (Weiss, Ure et al. 1980; Kiel, Felson et al. 1987) and was thought to be potentially beneficial against other chronic illnesses such as heart disease and dementia (Bluming and Tavris 2009). A sharp decline in prescription of HRT occurred after the termination of the combination estrogen-progestin therapy arm of the Women's Health Initiative (WHI) in 2002 (Hing and Brett 2006). ...
... A sharp decline in prescription of HRT occurred after the termination of the combination estrogen-progestin therapy arm of the Women's Health Initiative (WHI) in 2002 (Hing and Brett 2006). Since 2002 the WHI has made a number of updated reports warning of the dangers of HRT, however careful review of the data reveals these dangers are largely unfounded in most women (Bluming and Tavris 2009). The only conclusive danger is that of an increased cardiac risk in women over the age 60 taking HRT for the first time, and only for the first year (Bluming and Tavris 2009). ...
... Since 2002 the WHI has made a number of updated reports warning of the dangers of HRT, however careful review of the data reveals these dangers are largely unfounded in most women (Bluming and Tavris 2009). The only conclusive danger is that of an increased cardiac risk in women over the age 60 taking HRT for the first time, and only for the first year (Bluming and Tavris 2009). There is no conclusive evidence that exogenous estrogens increase the risk of breast cancer (Bluming and Tavris 2009). ...
... " , indicating that the results of the study should be approached with caution , as their earlier interpretation seemed too simplified . Certain objections may be raised to the selection of patients in the study group, such as large age differences , but also to the time of HR introduction, the oestrogen doses, higher than those recommended today, and to the combined use of the medroxyprogesterone derivative which is at present contraindicated [6, 7]. Among 26,000 examined women, in whom an increased risk of myocardial infarction was diagnosed, neither was any necessity for cardiological intervention demonstrated (aortic-coronary bridging, coronary angioplasty ) nor an increased death threat. ...
In developed societies, the post-menopausal period covers approximately one third of a woman's life. The deficit of oestrogens observed during the post-menopausal period significantly affects the course of many metabolic processes, causing a number of diseases and in consequence diminishing quality of life. Among others, bones belong to oestrogen-dependent tissues. The deficit of the protective influence of oestrogens compromises the dynamic balance of the bone transformation process towards resorption, thus reducing bone mass and quality, while increasing the risk of low-energy fractures. In recent years, differing views on the application of oestrogen/gestagen therapy have reached the level of controversy. The results of numerous clinical studies are far from unequivocal, with the whole subject one of heated debate. It has been confirmed that hormonal therapy prevents bone quality deterioration, while opening a protective umbrella around the bone, reducing the risk of osteoporotic fractures. A rational approach to weighing possible advantages against possible risks and a thorough evaluation of a patient's health condition allows for optimal therapy selection.
... Dans ce cas toutefois, la majorité des situations correspondent à une double supplémentation à la fois en estrogènes et en progestatifs [26]. Les données de la littérature en ce qui concerne le déclin mnésique associé à la carence en estrogènes et l'effet préventif des THS, sont controversées [27]. Ainsi, certaines études font ressortir une altération de la mémoire qui peut être corrigée par un THS mais d'autres, au contraire, ne rapportent pas d'effet ou des effets délétères [17,28—30]. ...
Estrogens are neurotrophic and neuroprotective compounds. They originate from peripheral and cerebral sources. Hippocampus expresses nuclear and membrane estrogen receptors mediating dendritic spine development, synaptic plasticity and preventing elevation of intracellular Ca++ concentrations. This review examines clinical, animal and in vitro data consistently showing a preventive effect of estrogens on hippocampus-dependent memory decline with ageing. It gives a definition of phytoestrogens and presents the main data obtained in that area with these compounds. The data are consistent with those obtained with estradiol with positive and negative effects, even though the literature is scarcer. Phytoestrogens not always exhibit all estradiol-modulating effects on estrogen receptors. Several specific molecules can therefore be considered as Selected Estrogen Receptor Modulators (SERMs) and appear to be good neuro-SERMs candidates for the dietary prevention of hippocampus-dependant memory decline with ageing.
... Hormone replacement therapies (HRT) are routinely used in menopausal women to reduce the effects of diminished levels of circulating oestrogen. These treatments improve patients' quality of life and also prevent conditions such as osteoporosis, colon cancer and dementia (Bluming et al, 2009). Despite the advantages of HRT, a number of studies have highlighted that they may also increase the risk of diseases such as cardiovascular disease, breast cancer and stroke (Nelson et al, 2002). ...
Breast cancer is the most prevalent form of cancer in women and accounts for 519,000
annual deaths (WHO Statistics). It has long been established that oestrogen (E2) stimulates
tumour growth of oestrogen receptor (ER) positive breast cancer and is involved in the
pathogenesis of the disease. Consequently, therapeutic approaches targeting the ER were
developed. The use of endocrine therapy is an integral component in treating breast cancer
however resistance to such drugs is a major limitation. Unfortunately, even initially
responding tumours eventually develop resistance - acquired resistance.
The aim of this study was to determine which intracellular pathways may be important in
conferring acquired endocrine resistance. In order to do so, a three-stage MCF-7 cell model
emulating the clinical development of acquired endocrine was used. MCF-7/LCC1 (LCC1)
and MCF-7/LCC9 (LCC9) cells lines were derived from the oestrogen dependent and antioestrogen
sensitive MCF-7 cell line. LCC1 cells remain responsive to endocrine therapies
but their growth is not dependent on oestrogenic stimulus. LCC9 cells, on the other hand
are fully resistant to endocrine therapies and completely oestrogen independent.
A number of different cell membrane receptors and intracellular pathways have been
implicated in endocrine resistance including HER receptor family, PI3K/Akt & MEK/ERK
pathways. These pathways are of particular interest since they are able to activate ER in the
absence of oestrogenic stimulus. It is likely that several pathways may be important in
conferring resistance to endocrine therapies therefore the experiments in this study
focussed on the transcriptional regulation of HER receptors, the activation of the Akt
pathway and its implication to basic cellular processes.
Following E2 treatment (48h), HER2/3/4 mRNA and protein levels were reduced in MCF-
7 and LCC1 but not in the endocrine-resistant LCC9 cell line as measured by QRT-PCR
and Western blotting. The anti-estrogen fulvestrant (ICI 182,780) reversed the E2
modulation. A previous study has shown that ER and the HER2 promoter compete for
limiting amounts of SRC-1 in oestrogen-responsive ZR-75-1 cells, causing HER2
repression after E2 stimulation (Newman et al.,Oncogene, 19, 490-7, 2000). ER RNAi
abolished E2 repression of HER2 in MCF-7 and LCC1 cells. Furthermore, LCC9 cells have
reduced SRC-1 recruitment to ER (assessed by ChIP) allowing SRC-1 to bind to the HER2 promoter. SRC-1 RNAi reduced HER2 transcription in MCF7 cells in a manner similar to
E2 whilst it did not restore E2 repression in LCC9 suggesting that the latter cells have
alternative mechanisms regulating HER2 transcription. RNAis against the other two p160
co-activators TIF2 and AIB1 did not restore E2 mediated HER2 repression in LCC9 cells.
The importance of redundancy between p160 co-activators was also determined by
performing double knockouts. SRC-1/TIF2 and TIF2/AIB1 double siRNAs had little effect
on HER2 mRNA levels however SRC-1/AIB1 siRNA restored oestrogen mediated
downregulation of HER2 transcription in LCC9 cells. This data indicates that SRC-1 and
AIB1 co-activators play a role in the transcriptional regulation of HER receptor
particularly in MCF-7 and LCC1 cells. The regulation of this transcriptional mechanism is
altered in resistant LCC9 cells but, as evidenced by the double knockouts, p160 coactivators
are still able to affect HER expression in these cells. This mechanism was
further studied in primary breast cancer tumour material.
The importance of the Akt pathway in this cell line model was also investigated as
phospho-Akt levels are elevated in LCC1 and LCC9 cells. This in turn was shown to
activate mTOR and ER (Ser167 residue phosphorylation) thereby contributing to increased
growth and ligand independent activation of the oestrogen receptor respectively.
Activation of PI3K and PTEN is unchanged in LCC1 and LCC9 cells suggesting that these
proteins are not responsible for elevated Akt phosphorylation. In contrast, these cells do
express higher levels of phospho-IGFR due to the high availability of receptor ligands
(IGFI & IGFII). This is likely to be, at least partially, responsible for the elevated Akt
activation. Moreover, the role of Akt isoforms was also determined as they are known to
have different functions. The levels of Akt 2 phosphorylation are higher in endocrine
resistant cell lines in comparison to parental MCF-7 cells. Interestingly, the Akt 3
phosphorylation is present in all cell lines whilst Akt 1 phosphorylation is minimal.
Nevertheless, Akt RNAi studies reveal that Akt 1 and 2 siRNA dramatically reduce growth
in MCF-7, LCC1 and LCC9 cells. These results suggest that Akt 2 phosphorylation may
play a part in conferring endocrine resistance but the other isoforms are also important for
normal cellular growth.
The cell cycle profiles of LCC1 and LCC9 are very similar to MCF-7. Similarly, migration
levels are unchanged in endocrine resistant cell lines. However, in the presence of antioestrogenic
drugs, apoptosis in LCC1 and LCC9 cells in reduced in comparison to the parental MCF-7 cell line. Furthermore, LCC1 and LCC9 cells have higher invasion rates.
The deregulation of HER receptor expression and elevated Akt activation may together
confer survival advantage in LCC1 and LCC9 cells whilst also increasing their invading
potential.
... In addition, hidden costs associated with management of side effects or other untoward effects caused by these treatments may significantly alter annual individual and population costs for these therapies. For example, estrogen-only therapy was the least expensive; however, women taking estrogen only have an increased risk of uterine cancer [10]. Additional costs associated with the management and treatment of an increase in incidence of cancer may surpass the costs of the alternative estrogen-progestin therapies. ...
Hot flashes are the cardinal symptom of menopause and can be treated with hormonal and nonhormonal prescription medications. However, considering that 6000 women enter menopause daily in the USA, and many of these women are symptomatic, the costs of these treatments can be a significant public health issue. We evaluated annual individual and population costs of hormonal and nonhormonal prescription treatments for hot flashes. Cost information may be helpful to clinicians and consumers in making treatment decisions.
