Proximate mechanism
Malignant neoplasms of the breast are most commonly derived from the epithelial lining of the ducts and lobules, thus classified as ductal or lobular carcinomas. The susceptibility to carcinogens is directly related to the epithelial cell proliferation rate and inversely related to the degree of tissue differentiation. Full maturation of the breast tissue only occurs after the first pregnancy (Russo et al. 2000), while breastfeeding may allow for the exudation of pre-neoplastic cells.
Malignancies of the ovary are in most cases derived from the ovarian epithelium (although some originate in fallopian tubes); few arise from egg cells or supporting cells. Like in any other cancer, a series of somatic mutations or epimutations is required for the neoplastic potential to be expressed (Greaves 2000).
Affected population
Breast cancer is the most common malignancy in women, and its incidence has been on the rise in the last several decades (Jemal et al. 2010). Primary risk factors for breast cancer include female gender, age over 50 (peri- and postmenopausal period), nulliparity or no breastfeeding, hormone-replacement therapy, obesity (but only in postmenopausal women), alcohol intake, tobacco exposure, exposure to endocrine disruptors, shift work and lack of exercise (Rossouw et al. 2002; The ESHRE Capri Workshop Group 2011). Diet, especially high animal fat intake, has been suggested but has not been proven as an independent risk factor.
Genetic factors also have an impact on risk, although the most common mutations account for only 2–3% of breast cancers. Best known is the high (up to 87%) risk of lifetime breast cancer in women carrying one of numerous loss-of-function mutations in the BRCA1 and BRCA2 tumor suppressor genes (Thompson et al. 2002; The Breast Cancer Linkage Consortium 1999). Since molecular phylogeny studies suggest that many of the most common alleles at BRCA1 and BRCA2 arose as new mutations in the relatively recent (tens of generations) past (Slatkin and Rannala 2000), the prevalence of these apparently deleterious alleles and their persistence in the population raises some interesting issues. Although most of the excess mortality in carriers of BRCA1 and BRCA2 mutations occurs late in life, after the reproductive period, sufficient cases occur earlier in life such that negative selection might be expected to act to decrease the frequency of the deleterious alleles. That this is not occurring suggests that the mutations also display beneficial (fitness-enhancing) effects in the reproductive period that trade off against their negative (increased cancer susceptibility) effects in later adulthood, a process known as antagonistic pleiotropy. Indeed, a recent study indicated that under natural fertility conditions, women carrying BRCA1/2 mutations had markedly increased fecundity (and, as expected, increased post-reproductive mortality) compared with controls (Smith et al. 2011). The increased fecundity was actualized by decreased interbirth interval and a longer reproductive period (greater age at last birth); the proximate (molecular) mechanisms relating altered function of BRCA1/2 to increased fecundity remain unclear.
While ovarian cancer is much less frequent than breast cancer, with an incidence rate of around 3% in the female population, the high mortality associated with this disease makes it one of the top five causes of cancer death among women in many developed countries (Jemal et al. 2010). Primary risk factors include age, nulliparity or no breastfeeding, no history of oral contraceptives, history of hormone-replacement therapy, and obesity. Genetic factors also play a role, as women with a first-degree relative who has developed the disease have a greater risk, which increases further when two or more relatives have been affected. Furthermore, BRCA1 and BRCA2 mutations are associated with an increased risk of ovarian cancer; mutations in these genes confer a lifetime risk of ovarian cancer of up to 66% (Thompson et al. 2002; The Breast Cancer Linkage Consortium 1999).
Evolutionary history, ultimate explanation, and demonstration of evolutionary principles
Epidemiological evidence indicates that late menarche, early first birth, high parity, early menopause, prolonged lactation reduce the risk of breast as well as ovarian cancer (Eaton et al. 1994). While all of these features characterized women in the Paleolithic as well as modern day hunter–gatherers, modern Western women have early menarche, a large gap between menarche and first birth, low parity, and relatively short lactation.
While the postponement of reproduction, low parity, and short lactation are outcomes of social, economic, and political developments that began in the nineteenth century, lowering of the age at menarche is a phenomenon that needs explanation from the evolutionary perspective. In the developed world, the age at menarche has fallen from 17 in the nineteenth century to about 12.5 years in the late twentieth century (Whincup, Gilg et al. 2001; Parent et al. 2003; Gluckman and Hanson 2006; Papadimitriou et al. 2008). It has been suggested that improved nutrition played a major role in this phenomenon. Change in the age at menarche is one of the life history-associated set of mechanisms that shows plasticity due to environmental modulation (see Box 2, Pathway 2). A child exposed to placental insufficiency or poor nutrition in utero may anticipate a hostile external environment, sometimes including early death and consequently trade off intrauterine growth for survival to birth and (eventually) early puberty. At the same time, a fetus and child fed plentifully is able to increase fitness by extending the length of the reproductive period in both directions. So both underfed and well fed children start menarche early (Parent et al. 2003; Sloboda et al. 2007; Papadimitriou et al. 2008). Yet, in later life, the length of the reproductive period as well as the physiological markers of reproductive function markedly differs (Jasienska et al. 2006a, b). Indeed, a recent study of natural selection in a contemporary population has found that the age at menopause is increasing (Byars et al. 2010).
The increased age at first birth, low number of births, and short breastfeeding are all part of change in reproductive behavior that began in the West with the demographic transition about two centuries ago, but is today underway in many parts of the world, in particular in East Asia (Frejka and Sardon 2004; Frejka et al. 2010). Hunter–gatherers with menarche at 16, average first birth at about 19.5, breastfeeding for the first three or four years of the child’s life, an average completed family size of five or six live births, and menopause at around 47 years of age, experience only about 188 ovulations (Eaton et al. 1994). Among the Dogon of Mali, a traditional farming West African population with a mean of 8.6 ± 3 live births per woman, women aged 20–34 years had a median of only two menses each over the two-year study period. Their median number of menses per lifetime was just 100 (Strassmann 1999). Modern women, by contrast, have menarche at 12.5, first birth at 24–27 years of age, and a completed family size of 1.8, so by the age of menopause at 47.5 they may experience close to 500 ovulations (Eaton et al. 1994). The high number of ovulations, it has been argued, mechanically injures the ovarian epithelium while exposing it to locally high hormonal levels, and so increases the risk of ovarian cancer. The reduction of the ovarian cancer risk associated with oral contraceptive use is probably at least partly explainable by ovulation suppression (Siskind et al. 2000). With regard to breast cancer, the lack of full maturation of breast tissue in nulliparous women as well constant proliferative stress on the ductal and lobular epithelium by estrogen and progesterone leads to higher rates of carcinogenesis. The use of hormone-replacement therapy, shown to increase the risk of breast cancer, extends the exposure to estrogen and progesterone (Rossouw et al. 2002). At the same time, reduced lactation also removes the beneficial loss and renewal of ductal epithelial cells by lactational “washout”.
Pathways of altered disease risk illustrated by this example
-
An evolutionarily mismatched or novel environment. The marked change in human reproductive behavior, involving the use of contraception and hormone-replacement therapy, nulliparity, few and late pregnancies as well as reduced lactation, has created a novel female endocrine environment that differs from the environment in which we evolved, an environment of pregnancy and/or lactational amenorrhea for the majority of fertile years. The novel environment has exposed vulnerability to the carcinogenic effects of sex hormones. The loss of the protective mechanisms associated with pregnancy, lactational amenorrhea, and washout as well longer lifetime exposure to ovulating ovaries has allowed potentially damaged cells to be retained and turn malignant.
-
Life history and trade-off associated factors. The fall in the age at menarche, driven by improved nutrition, has extended the potential reproductive period, yet it has also increased the time that the breast and the ovarian epithelia are exposed to the mechanical and endocrine effects of ovulation. Furthermore, because the human life span is now much longer and there is an age-related linear increase in the risk of cancer detected in postmenopausal women, the total lifetime risk of cancer becomes much larger. Finally, the effects of BRCA1/2 mutations on fecundity and cancer susceptibility provide an excellent example of antagonistic pleiotropy, trading off increased reproductive fitness against impaired somatic maintenance (tumor suppression).
-
Selection operates by maximizing fitness. For all cancers, neoplastic progression represents a Darwinian process of mutation, variation, and selection among cell lineages within individuals, such that tumor cell lineages with enhanced survival or proliferation capacity will outcompete less “fit” lineages. Such microevolutionary factors play a role in the development of resistance to cancer therapy, and understanding the selection pressures and trade-offs involved may lead to new treatment approaches.