Endometriosis as a model for inflammation–hormone interactions in ovarian and breast cancers
Introduction
Chronic inflammation induced by infections and irritants has been implicated in one-sixth of incident cancers worldwide.1, 2, 3 Just a few examples of non-infectious, chronic inflammants and linked cancers include asbestos fibres and mesothelioma;4 inflammatory bowel disease and colon cancer; and mastitis and breast cancer.5 Previously, we proposed that inflammatory exposures may also promote the development of ovarian cancer.6, 7 These examples all involve inflammation and tumour development within the same tissue. Systemic inflammatory diseases and their treatments (e.g., rheumatoid arthritis and TNF-α therapy) have generally been linked to lymphoproliferative, rather than organ-specific malignancies.8
In this review, we consider associations between endometriosis, defined by the presence of endometrial foci outside the endometrium, and cancers both local (ovarian) and distant (breast). We suggest that endometriosis may promote both tissue-specific and systemic alterations in sex steroid hormones and inflammatory mediators. Thereby, endometriosis may represent a model, wherein inflammatory–hormonal interactions promote both local and distant carcinogenesis.
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Epidemiological data linking endometriosis, ovarian cancer and breast cancer
Epidemiological studies have consistently supported a link between endometriosis and cancer. Brinton and colleagues assessed cancer outcomes among 20,686 women in Sweden who had been hospitalised with endometriosis.9 Cancer outcomes were identified through the National Swedish Cancer Registry after a mean of 11.4 years of follow-up. Significant excess risks were observed for ovarian cancer (standardised incidence ratio 1.9, 95% confidence interval (CI) 1.3–2.8), breast cancer (1.3, 1.1–1.4) and
Clinical data linking endometriosis and ovarian cancer
Although, to our knowledge, the only clinical data that demonstrate an association between endometriosis and breast cancer are studies showing that women using tamoxifen for breast cancer may develop endometriosis (presumably on the basis of a pro-oestrogenic effect (see below))20, 21 there are compelling clinical data relating endometriosis and ovarian cancer. Pathological case series have provided evidence for the transformation of endometriosis into malignancy.22, 23, 24, 25, 26, 27, 28, 29,
Inflammation and cancer
How might endometriosis elevate the risk of both local and distant cancers? We propose a mechanism influenced by inflammation and steroid hormones. Chronic inflammation results in oxidative stress,37 necrosis and compensatory cell division. Rapid cell division gives rise to an even greater need for DNA repair with its attendant potential for replication errors, which, particularly when they occur at key regulatory sites, such as p53, increase the risk of mutagenesis.1 Finally, inflammation
Hormones in breast and ovarian cancer
Oestrogens, progesterone and androgens are all believed to contribute to breast cancer development, especially in post-menopausal women121, 122, 123, 124, 125, 126 Early menarche, late menopause and length of reproductive life, factors consistent with prolonged exposure to endogenous oestrogens, have consistently been associated with an increased risk of breast cancer in post-menopausal women.127 In older post-menopausal women, serum concentrations of oestradiol predict the risk of breast
Endometriosis: interaction between inflammation and hormones
Altered immune function in women with endometriosis is ubiquitous, may favour the growth and progression of endometriosis, and upregulates local oestrogen, a major driver of endometriosis. Sites of endometriosis are surrounded by peritoneal inflammatory cells,186, 187, 188 but rather than clearing the ectopic endometrium, these cells (e.g., natural killer (NK) cells) express reduced cytotoxicity.189, 190, 191 Resection of endometriotic foci increased the percentage of moderately differentiated
Sex hormones and inflammation in relation to breast and ovary cancer
Inflammatory mediators have emerged as important regulators of oestrogen synthesis in breast tissue as well. IL-6 levels increase the activity of aromatase in breast and adipose tissue, thereby directly increasing systemic and local breast oestrogen levels.242 Within the breast, TNF-α can also act alone243 or synergistically with IL-6 to enhance the activities of aromatase244 E2DH245, 246 and oestrone sulphatase247 the three enzymes involved in the production of oestradiol from androstenedione,
Cytokines and hormones interact in the ovary
There is also mounting evidence of hormone–cytokine interactions within the ovary. For example, ovulation involves increased production of TNF-α, IL-1β, IL-6 and COX-2.260, 261, 262 Indeed, the anti-inflammatory NSAIDs inhibit human ovulation.263 Ovarian cancers are thought to arise within inclusion cysts, epithelium that folds into the stroma as surface cells are entrapped in the ovarian wound created during ovulation. This brings epithelium into close proximity with stromal inflammatory
Summary
Endometriosis is associated with both ovarian and breast cancers. The relationship with ovarian cancer can be understood as a local process of malignant transformation, whereas the relationship with breast cancer cannot. Sex steroid hormones and inflammation have been implicated in the pathogenesis of each of endometriosis, ovarian cancer and breast cancer. A possible explanation for the association between endometriosis and these reproductive cancers is one of local and systemic enhancement of
Conflict of interest statement
None declared.
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