Abstract P4-04-02: Cell death and efferocytosis generate a pro-metastatic landscape during mammary gland involution that increase dissemination of post-partum breast cancers
Authors: Cook Rebecca S , Earp Shelton , Stanford Jamie 
Published: May 2015

Although pregnancy at a young age decreases a woman’s lifetime breast cancer risk, the first five years following a pregnancy at any age are associated with increased breast cancer risk, a risk that continues to increase with age. Given societal trends to postpone child-birth later into women’s lives, the incidence of malignant post-partum breast cancer is expected to increase. Currently, breast cancers diagnosed 2-5 years post-partum account for nearly 25% of all pre-menopausal breast cancers. Importantly, breast cancers diagnosed 2-5 years post-partum are diagnosed more frequently as metastatic disease and correlate with decreased disease-free survival (DFS) versus breast cancers occurring in other young pre-menopausal women. In contrast, many studies show that breast cancers diagnosed during pregnancy do not correlate with decreased DFS, although there remains some debate about this conclusion. The observation that post-partum breast cancers correlate with reduced DFS suggests that events occurring in the post-partum breast augment the malignant severity of tumors existing therein. This hypothesis is supported by studies in which breast cancer cells transplanted into involuting mouse mammary fatpads grow and invade more rapidly than cells transplanted into mammary glands of nulliparous mice, demonstrating a unique mammary micro-environment during involution versus other reproductive stages. We aimed to study how the changing landscape of the post-partum breast accelerates cancer progression.

Although the molecular mechanisms underlying the malignant severity of post-partum breast cancers (ppBCs) are unclear, they relate to stromal wound healing events during post-partum involution, a dynamic process characterized by widespread cell death in milk-producing mammary epithelial cells (MECs). Using both spontaneous and allografted mammary tumors in fully immune-competent mice, we discovered that post-partum involution increased mammary tumor metastasis 10-fold. Widespread cell death occurred not only in MECs, but also in tumor epithelium. Dying tumor cells were cleared through MerTK-dependent efferocytosis, which robustly induced transcription of wound healing cytokines interleukins (IL)-4, -10, and -13, and transforming growth factor (TGF)-beta. Genetic models of MerTK ablation and pharmacologic MerTK inhibition impaired efferocytosis in post-partum tumors, reduced M2-like macrophages without altering total macrophage levels, decreased TGF-beta expression and reduced post-partum tumor metastasis to levels seen in nulliparous mice. TGF-beta blockade reduced post-partum tumor metastasis. These data suggest that widespread cell death during post-partum involution triggers efferocytosis-induced wound healing cytokines in the tumor microenvironment that promote metastatic tumor progression.

Citation Format: Rebecca S Cook, Shelton Earp, Jamie Stanford. Cell death and efferocytosis generate a pro-metastatic landscape during mammary gland involution that increase dissemination of post-partum breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-04-02.