The protective effect of pregnancy is neither immediate nor constant — a transient increase in breast cancer risk occurs with pregnancy in women of all ages. The risk of pregnancy-associated breast cancer is greatest in older first-time mothers.
Pregnancy-associated breast cancer has a higher mortality rate because metastasis is common. Possible reasons for breast cancer metastasis with pregnancy include the promotional effects of pregnancy-associated hormones and a delay in diagnosis in recently-pregnant women. However, existing data indicate that these factors do not account for the high mortality associated with pregnancy-associated breast cancer.
Following pregnancy and lactation, the mammary gland regresses to its pre-pregnant state by a tissue remodelling process known as involution. The microenvironment of the involuting mammary gland shares attributes with inflammation and wound healing.
Because pro-inflammatory tissue environments can promote tumorigenesis, the involuting mammary gland might be tumorigenic. Candidate mediators of tumour cell progression during gland involution include an influx of activated immune cells, increased concentrations of matrix metalloproteinases, remodelling of mammary extracellular matrix with subsequent release of tumour-promoting growth factors and matrix fragments with bioactivity, and loss of basement-membrane barrier function.
Under normal conditions of involution, pro-inflammatory pathways are activated, but the balance of pro- to anti-inflammatory signals is tipped towards suppression of overt inflammation.
The presence of occult disease at the time of gland involution is anticipated to aggravate the tumour-promoting microenvironment by tipping the balance towards overt inflammation. So, women with occult disease at the time of pregnancy might be at an increased risk of tumour cell dissemination during mammary gland involution.
As the average age of child-bearing continues to rise, the incidence of pregnancy-associated breast cancer and its associated high mortality rate are also anticipated to rise.
Pregnancy-associated breast cancer, which has a poor prognosis, is often overlooked by clinicians and researchers alike. With the trend towards delayed child-bearing, an increase in the occurrence of breast cancer complicated by pregnancy is anticipated. The mechanisms that have been proposed to account for this poor prognosis, including increased hormone exposure, might not contribute significantly to the observed increase in metastasis seen in these patients. Instead, the mammary microenvironment might become tumour-promoting after pregnancy because of the remodelling of the mammary gland to its pre-pregnant state. This remodelling, which is associated with pro-inflammatory and wound-healing mechanisms, is proposed to support tumour-cell dissemination. This hypothesis will be discussed.
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The author would like to thank Tim E. Byers and Peter Henson for critical and insightful review of the manuscript, Grethe Albrektsen for providing access to her pregnancy-associated breast cancer cohort data and for lively discussions, and Yan-Gao Man for his generous contribution of the human DCIS micrographs shown in figure 4. This work was supported by grants from the National Cancer Institute. This manuscript is dedicated to the memory of Greer Page, whose battle with pregnancy-associated breast cancer inspired these studies.
The author declares no competing financial interests.
National Cancer Institute
- Relative risk
An epidemiological measure of treatment effect in an intervention study (clinical trial) or exposure association in a non-experimental observational study. The relative risk is the ratio of risk in an exposed group (that is, recent birth group) to the risk in an unexposed, control group (no recent birth).
- Innate immune response
Innate immunity is the first line of defence against injury and is mediated by the myeloid lineage cells, primarily the dendritic cells, neutrophils and monocytes. The trigger of innate immunity can be conserved microbial molecules, such as LPS, or chemokines and cytokines. The result of activating the innate immune response is killing of microbes and recruitment of additional immune cells through cytokine mediators.
- Adaptive immune response
Adaptive immunity — also known as acquired immunity — is the second line of defence mediated by cells of the lymphoid lineage, the T cells and B cells. Adaptive immunity is subordinate to innate immunity because activation relies on innate immune cells for antigen presentation.
- Acute-phase response
The acute-phase response is the systemic inflammatory component of innate immunity and comprises the non-specific physiological and biochemical response to tissue damage. The acute phase response was first described in the liver, which, in response to circulating cytokines released at the site of pathology, rapidly synthesizes a number of immunomodulatory proteins, including C-reactive protein, amyloid A protein, proteinase inhibitors, and coagulation and complement proteins.
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Schedin, P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer 6, 281–291 (2006). https://doi.org/10.1038/nrc1839
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