Mammary gland involution as an immunotherapeutic target for postpartum breast cancer

Abstract

Postpartum mammary gland involution has been identified as tumor-promotional and is proposed to contribute to the increased rates of metastasis and poor survival observed in postpartum breast cancer patients. In rodent models, the involuting mammary gland microenvironment is sufficient to induce enhanced tumor cell growth, local invasion, and metastasis. Postpartum involution shares many attributes with wound healing, including upregulation of genes involved in immune responsiveness and infiltration of tissue by immune cells. In rodent models, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) ameliorates the tumor-promotional effects of involution, consistent with the immune milieu of the involuting gland contributing to tumor promotion. Currently, immunotherapy is being investigated as a means of breast cancer treatment with the purpose of identifying ways to enhance anti-tumor immune responses. Here we review evidence for postpartum mammary gland involution being a uniquely defined 'hot-spot' of pro-tumorigenic immune cell infiltration, and propose that immunotherapy should be explored for prevention and treatment of breast cancers that arise in this environment.

Fig 1

Serial sections of human involuting breast tissue demonstrate immune cells in very close proximity to breast epithelium. Representative immunohistochemical staining (brown) for the epithelial cell marker cytokeratin 18 (CK18), the general leukocyte marker CD45, and the macrophage marker CD68 are shown. CD45 and CD68 positive cells within the breast epithelium are indicated with arrows and arrowheads, respectively. Modified with permission from O’Brien et al. [39]

Fig 2

Epithelial regression and adipocyte repopulation during postpartum involution in the rat mammary gland. Hematoxylin and eosin staining of rat mammary tissue generated as described [39]. Vir = virgin, Preg = pregnancy day 18, Lac = lactation day 10, Inv2–10 = 2–10 days post-wean, Reg = Regressed (4 weeks post-wean)

Fig 3

Postpartum involuting lobules have increased immune cell infiltrate. Immunohistochemical staining for the general leukocyte marker CD45, the macrophage marker CD68, the B cell marker CD19, and the T cell markers CD4 and CD8 in actively involuting (Inv) and lactating (Lac) human breast tissue lobules. Scale bar = 100 μM; inset = representative positively-stained cell at 6× magnification of the larger image

Fig 4

Macrophages as orchestrators of a tumor-promotional immune environment during postpartum mammary involution. Alternatively activated macrophages, characterized by mannose receptor and arg-1 expression, increase in the mammary gland during involution. Involution macrophages are anticipated to contribute to tumor promotion directly through the production of growth factors, such as epidermal growth factor (EGF) [176], and indirectly by suppressing anti-tumor immunity. Targeting macrophage recruitment and activation may be one way to alleviate macrophage-induced tumor promotion during postpartum involution. Involution macrophage recruitment and activation are anticipated to be promoted by ECM components, cytokines, growth factors, and prostaglandins, all of which represent potential immunotherapeutic targets directed toward involution macrophages