Clearance of dying cells accelerates malignancy

The breast endures vast changes during reproductive phases of a woman's life (puberty, pregnancy, lactation, post-partum involution, post-menopausal involution). Each phase uniquely shapes cancer susceptibility, formation, and progression. Although pregnancy at a young age decreases lifetime breast cancer risk, the first five years following pregnancy at any age are associated with increased breast cancer risk regardless of the woman's age, and with even greater risk with increasing age at the woman's first pregnancy [1]. Increasingly, women are postponing childbirth , which may increase the incidence of post-partum breast cancer (ppBC), defined as those breast cancers diagnosed 2-5 years after pregnancy. These ppBCs are distinguishable from those breast cancers that are diagnosed and treated during pregnancy, and which never are exposed to post-partum/post-lactational involution, and which correlate with a favorable prognosis. Currently, ppBC accounts for nearly 25% of all breast cancers in young (pre-menopausal) women. In contrast, ppBCs are highly aggressive, metastatic, and life-threatening, even when corrected for molecular breast cancer subtype and for the age of the woman at diagnosis [1]. Mouse models of ppBC that specifically compare mammary tumors from nulliparous (virgin) mice to those from age-matched parous (single pregnancy) mice confirm that post-partum involution increases metastasis by up to 10-fold [2,3]. The molecular mechanisms underlying the exaggerated lethality of post-partum breast cancers are related to an exaggerated abundance of M2-like tumor associated macrophages, which produce immune suppressive and wound healing cytokines and proteases that modify the post-partum mammary (and tumor) microenvironment [4], although the mechanisms that trigger this shift in macrophage behavior in the post-partum mammary gland remained obscure. It was recently demonstrated that widespread cell death, a hallmark of the mammary gland during post-partum involution when milk production ceases, triggers macrophage-mediated efferocytosis, M2 macrophage polarization and Th2 cytokine production in normal mammary glands during post-partum involution [5]. Remarkably, widespread cell death efferocytosis, macrophage M2 polarization, and Th2 cytokine-mediated wound healing in malignant post-partum breast cancers was similarly observed [3]. Under physiological conditions, dying cells are rapidly removed from the breast to prevent secondary necrosis of the dying cell, wherein intracellular antigens released from the necrotic cell might trigger inflammation, tissue damage, or autoimmunity [6]. To ensure suppression of inflammation or autoimmunity, efferocytosis is coupled with production of cytokines that dampen tissue-damaging immune responses, such as interleukin (IL)-10, IL-4, and Transforming Growth Factor (TGF)-β [7]. Macrophages use multiple cell surface protein to recognize and engulf dying cells. Among …