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.

Recent pregnancy correlates with decreased survival for breast cancer patients compared with non-pregnancy-associated breast cancer. We hypothesize that postpartum mammary involution induces metastasis through wound-healing programs known to promote cancer. It is unknown whether alternatively activated M2 macrophages , immune cells important in woundhealing and experimental tumorigenesis that also predict poor prognosis for breast cancer patients, are recruited to the normal involuting gland. Macrophage markers CD68 , CSF-1R , and F4/80 were examined across the pregnancy and involution cycle in rodent and human mammary tissues. Quantitative immunohistochemistry revealed up to an eightfold increase in macrophage number during involution , which returned to nulliparous levels with full regression. The involution macrophages exhibit an M2 phenotype as determined by high arginase-1 and low inducible nitric oxide synthase staining in rodent tissue , and by mannose receptor expression in human breast tissue. M2 cytokines IL-4 and IL-13 also peaked during involution. Extracellular matrix (ECM) isolated from involuting rat mammary glands was chemotactic for macrophages compared with nulliparous mammary ECM. Although it is recognized that full-term pregnancy at an early age reduces the lifetime risk of developing breast cancer, women of all ages have a transient increase in breast cancer risk with a recent pregnancy.1-4 Breast cancers diagnosed up to five years out from a completed pregnancy have been referred to as pregnancy-associated or PABC. 5,6 Several studies have shown that PABC frequently metastasizes, resulting in poor prognosis for the patient.6 -8 Epidemiological data identify women whose breast cancer is diagnosed postpartum, rather than during pregnancy, as having the worst outcomes.7-14 Further, when breast cancer patients were matched for known prognostic indicators, the postpartum window proved to be an independent factor for metastasis, whereas a diagnosis during pregnancy did not. 11,14,15 We have proposed the involution-hypothesis to account for the high metastatic oc-