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June 2010 - December 2013
I - Breast cancer risk factors
13. Factors promoting breast cancer: hormones
Hormones are regulatory or stimulatory compounds produced and used by the body as a part of accomplishing certain functions, or for initiating and directing structural changes within tissues and organs. Hormonal activity generally decreases into adolescence and adulthood, with the exception of the periodic ovarian hormones function regulating the reproductive cycle in females.
It is ovarian hormones - and particularly estrogens - that are commonly taking the spotlight as the hormonal breast cancer risk factor. However, other sources of exposure to hormones that tend to promote breast cancer growth - hormonal medical treatments, environmental estrogens, growth hormones, hormones produced by fat tissues, insulin and insulin-like growth factor (IGF) - shouldn't be neglected.
Beginning of the female reproductive cycle is marked by the onset of menarche, when a complex set of activities initiated by hypothalamus and pituitary gland, and carried out mainly by ovarian hormones - primarily estrogen and progesterone - results in the first menstrual period. From then on, the female body repeats this ovulation cycle approximately every month, producing and disposing of ovarian hormones in the process (hence body estrogen levels depend not only on the rate of its production, but also on how efficiently body disposes of it "after use").
This continues until the menopause, and represents the main source of female's lifetime exposure to estrogen. The earlier the onset of menarche, and the later the menopause, the longer i.e. greater the exposure for a given hormonal production level.
Normally, this reproductive cycle is interrupted only by a pregnancy. Any pregnancy reduces the lifetime estrogen exposure, but early ones - particularly before age 20 - are most beneficial, because they come at the time when some breast tissues (intralobular terminal ducts) are still highly undifferentiated, and also with high rate of proliferation, thus highly susceptible to carcinogens.
Estrogen has no role in initiating breast cancer (mutation and carcinogenesis may occur due to proliferation itself, from accumulated DNA replication errors, but the chances for that to occur are extremely small); however, once the cancerous cells form,
it promotes their multiplication.
The lifetime estrogen exposure of the modern women - particularly in the developed Western countries - is significantly higher than what is was in the 19th century, and earlier, and what it is at present in most of undeveloped countries. Part of it is due to the earlier onset of menarche, later menopause and fewer and more delayed childbirths. The other part is the more plentiful, high-caloric Western diet, stimulating the overall hormonal activity, particularly during childhood and adolescence.
Breast cancer risk due to higher endogenous estrogen exposure is
generally lower than that related to the family history of breast
cancer: it ranges from up to 30% higher for early menarche, to up to
90% higher for having first child after the age of 30, or no
childbirths, as opposed to family history ranging from up to 50%
higher risk for having 2nd-degree relative with breast cancer to 3.6
times higher, statistically, for two
Considering this and other facts (e.g. very low chances for breast cancer to develop primarily as the result of accelerated cellular proliferation), the increase in the endogenous estrogen exposure
can be only among the secondary causes of the
that started in the second half of the 20th century. For the primary causes we have to look at the increased exposure to breast cancer initiating factors - especially ionizing radiation and chemical carcinogens - as well as the combined effect of the multitude of predisposing and promoting factors.
Longer term exposure to medications with estrogenic activity, such as those administered in a hormone replacement therapy, birth control pills and the very drugs used for breast cancer treatment/prevention, like tamoxifen and raloxifene, can present significant risk factor for some women.
Another example of a big marketing scheme approved by the FDA without making sure it's safe, hormone replacement therapy, just can't shake off all kinds of adverse effects popping up no matter what hormone combination drug manufacturers try with.
From the mid-1970s it's been known that the initial estrogen-only therapy significantly increases the risk of uterine cancer (Smith et al. 1975, Ziel and Finkle 1975, etc.). To alleviate that, progesterone is added but, turned out, this combination significantly increased breast cancer risk (Nurses Health Study, Colditz et al. 1990/1992).
And so did adding testosterone, or, more recently, tibolone (drug releasing synthetic steroid hormones). Table below summarizes results of the largest studies on the HRT effect on breast cancer risk to date.
P=progesterone, Ti=tibolone, D=deaths from
The studies are consistent in showing the increased risk of breast cancer for women on HRT, with the exception being women after hysterectomy (Chen et al. indicates increased risk for these women too, but only with treatment significantly longer than 10 years). The increase is mainly moderate, not supporting the notion that HRT is a major contributor to breast cancer incidence. However, it is significant enough to label HRT as the risk factor.
Worth mentioning is that other significant adverse effects of HRT include cardiovascular disease, thromboembolism, endometrial cancer, ovarian cancer, cholecystitis (gallbladder inflammation), gastroesophageal reflux (Jacobson et al. 2008) and brain atrophy. Two large recent studies - WHI 2003 and WHI 2006 from the above table - were terminated early because of the
unacceptable health risk to participants
created by hormonal treatments they were subjected to. In the former, it was due to unacceptable rate of invasive breast cancer, but also coronary heart disease (1.29 risk ratio, estrogen users), stroke (1.5) and thromboembolism (2.14, estrogen users). In the latter, it was due to the significantly increased incidence of stroke.
The bad numbers could be actually worse, since it is recognized that women undergoing HRT are not exactly your next door menopausal women: they tend to be generally healthier (in part due to the guidelines advising to recommend it to women w/o significant health problems), leaner, more physically active, with higher than average living standard and eating healthier. In short, at a generally lower risk of developing breast cancer - and pretty much any other disease - or dying from it.
Also, hormonal therapy causes breast tissue to become denser, harder to see through on mammograms, which lowers cancer detection rate in that population of women. Thus it can be expected that their BC incidence rate, based on the detection, has some lag which, if not accounted for, can make it appear lower than what it really is.
What makes the numbers more uncertain is that the reality of these studies - particularly those observational - is that they at best establish sufficiently accurate
The problem is, such associations can be grossly inaccurate reflections of the actual causative relationships.
One such possible false association is fairly consistent finding that breast cancer risk in HRT users decreases with the increase in body mass index (BMI), an indicator of overweight/obesity. Leaner women - but not underweight - should have less cancer-fueling estrogen, since it is in part produced in the fat tissue.
Possible answer to this puzzling association is that the excess of breast cancers in lean women is, at least in part, the consequence of it being easier and earlier diagnosed in the leaner tissue by the routine diagnostic screening (1985 NHS study by Willet et al. found that the excess of breast cancers in lean premenopausal women was limited to well-defined, early stage tumors smaller than 2cm in diameter).
Another piece of this puzzle likely has something to do with the carriers of ATM gene polymorphism - a rare disease sharply increasing the risk of breast cancer, making the proportion of its carriers in the breast cancer population relatively significant - which are typically undernourished and thin.
Yet another is the recent - somewhat contradictory - evidence suggesting that women who were lean in their childhood and adolescence tend to have significantly higher level of IGF (insulin-like growth factor hormone) - a breast cancer risk factor.
Environmental estrogens (xenoestrogens)
Next come estrogen mimics or environmental estrogens. Many pesticides and plasticizers/phthalates (chemicals used in production of all types of plastics) have molecular structure similar to body hormones. That gives them the ability to cling to the cellular hormonal receptors mimicking these hormones - in this case female hormones, primarily estrogen. Both, pesticides and plasticizers are widely present in the environment; for most people, the main exposure window is food consumption (including liquids and water).
How small concentrations can be active in promoting cancerous growth is well illustrated by the accidental discovery of estrogenic potency of the common plastic test tubes. The researchers knew that adding estrogen fuels growth of cultured breast cancer cells, but were puzzled seeing accelerated growth in the tubes without any estrogen added. The culprit was soon found: it was the plasticizer leaking from the plastic that the tubes were made of - identified as bisphenol A10.
Any food packaged in plastic can be contaminated by endocrine disruptors leaking from it. In fact, no direct contact is needed: half a pound of cookies coming in a box with clear plastic window absorbs 4mcg of its phthalate emission from the air inside the box10. The body has poor ability to degrade or eliminate plasticizers, so they tend to accumulate with time.
Many foods naturally contain compounds structurally similar to estradiol (the major human estrogen) - so called phytoestrogens (which are grouped in isoflavones, lignans and coumestrol). Depending on their exact molecular structure, they can cause either estrogenic, or anti-estrogenic effect. Put simply, if such a molecule is similar enough to estradiol to fit in its cellular receptor, but not enough to have it activated, it will literally clog estrogen receptors, preventing estrogen molecules from binding to it,
thus acting as estrogen antagonist.
This implies that the effect of phytoestrogens on body's estrogenic activity is uncertain, being subject to both, specifics of the molecule itself, and the particulars of cellular "context", varying from one individual to another. However, the fact that foods containing phytoestrogens (nuts, oilseeds like flax and sesame, soy and soy products, grains, brassica vegetables family, including broccoli, rice and others) are part of a healthy diet and/or staples of diet in countries with the lowest breast cancer incidence rates, suggests that their overall negative effect with respect to breast cancer risk is unlikely.
Phytoestrogens also act as antioxidants, thus exerting protective effect against cancer in general.
Seemingly strange association fairly consistent in studies is one between increased breast cancer risk and body height. Probably the strongest association so far was found in a large cohort of Norwegian women; those taller than 167cm had as much as 2.63 higher breast cancer incidence than those below 159cm (Vatten and Kvinnsland, 1990a).
However, since body size is a direct result of hormonal activity - and, obviously, requires higher rate of cellular proliferation - the association is probably not just a statistical freak.
Also, body height could be positively correlated with body's IGF (insulin-like growth factor) levels, which not only has estrogenic effect itself, but also enhances activity of body estrogens. Whether other significant factors could also be related to this and other body type characteristics, and to what extent, remains to be determined.
In any event, body height or, more specific, its frame size, as a breast cancer risk factor is most likely related to elevated hormonal levels - which may include other promoters of cellular proliferation beside estrogens - thus belongs to the group of hormonal promoting breast cancer factors.
In most cases, obesity is directly related to diet. In general, it should always have negative effect, since adipose tissue generates estrogens by transforming adrenal androgen hormones, like testosterone, and increasing by that body's estrogen level.
Oddly enough, studies indicate that it is the risk factor only for postmenopausal women, while slightly protective for premenopausal women. Likewise, weight gain during adulthood increases the risk only for postmenopausal women. This apparent obesity-related risk increase for postmenopausal women is not dramatic (approximately in the 20-30% range), so it may still be statistical deviations, despite being, so far, fairly consistent.
One possible rationale for this logic-defying research result is that the additional estrogen generated by fat tissue is relatively insignificant with respect to body's premenopausal estrogen production, and that normally functioning ovaries can even - at least in part - compensate for it by lowering their production.
As the ovarian hormonal activity takes downturn after menopause, estrogen generated by fat tissues becomes more significant player, not in the sense that it causes nominally high estrogen levels, but more likely by
creating hormonal imbalance
(estrogen dominance) in the conditions of lowered ovarian hormonal production.
Another hypothesis is that obesity before menopause may be causing anovulations, reducing estrogen exposure. That can also occur as a result of extreme underweight, with both overweight and underweight being associated with somewhat lower risk of breast cancer. According to these results, maintaining healthy weight throughout adulthood could actually be a risk factor.
More than anything, these contradictions, so common in the breast cancer research, remind us of the complex nature of this disease, with many different factors, positive and negative, interacting to produce the final outcome. Studies that don't properly control for all the relevant factors - and hardly a single one had come even close to it - are doomed to end up with randomly skewed results.
Insulin and IGF
Insulin is a hormone-like substance best known for its role in glucose metabolism. It is needed for transport of glucose molecules into the cell, but it is also needed for transport of other nutrients; there is an entire family of insulin cellular receptors. However, elevated insulin levels are commonly caused by the elevated blood glucose levels, in which case it is clearing of glucose from the bloodstream that takes priority. Thus chronically elevated glucose/insulin levels may cause impaired cellular supply of insulin-dependent nutrients (one of them being vitamin C).
By supplying the cells with their preferred fuel - glucose - insulin stimulates cells to store fats. That, as we know, can spell trouble down the road, with both, weight gain and obesity being breast cancer risk factors.
But insulin body functions go beyond that. Chronically elevated insulin levels create complex signaling pathways affecting body's metabolic mode and gene expression. One of the consequences is switching to the higher oxidation states, with higher rate of cellular proliferation. That helps cancer grow.
And so does causing the special gene transcription proteins (FOXO) to move out of the cell nucleus, thus preventing them from doing their main job, which is modulating expression of genes regulating some vital cellular processes - like apoptosis (programmed cell death), cell-cycle progression and oxidative protection - based on environmental inputs (the "oxidative protection" part makes it also a cancer predisposing factor).
Insulin-like growth factor (IGF) has similar effect on cellular proliferation and FOXO proteins as insulin.
There are other negative consequences of chronically elevated insulin, but these are already more than sufficient to minimize the intake of sugar and other high-glycemic-index foods. With breast cancer, or without it.
Next are non-hormonal breast cancer promoting factors.