Targeting Obesity-Induced Macrophages during Preneoplastic Growth Promotes Mammary Epithelial Stem/Progenitor Activity, DNA Damage, and Tumor Formation

Abstract

◥Obesity enhances breast cancer risk in postmenopausal women and premenopausal women with genetic or familial risk factors. We have shown previously that within breast tissue, obesity increases macrophage-driven inflammation and promotes expansion of luminal epithelial cell populations that are hypothesized to be the cells of origin for the most common subtypes of breast cancer. However, it is not clear how these changes within the microenvironment of the breast alter cancer risk and tumor growth. Using a high-fat diet to induce obesity, we examined preneoplastic changes associated with epithelial cell-specific loss of Trp53. Obesity significantly enhanced the incidence of tumors of diverse histotypes and increased stromal cells within the tumor microenvironment. Obesity also promoted the growth of preneoplastic lesions containing elevated numbers of luminal epithelial progenitor cells, which were surrounded by macrophages. To understand how macrophage-driven inflammation due to obesity enhances tumor formation, mice were treated with IgG or anti-F4/80 antibodies to deplete macrophages during preneoplastic growth. Unexpectedly, depletion of macrophages in obese mice enhanced mammary epithelial cell stem/progenitor activity, elevated expression of estrogen receptor alpha, and increased DNA damage in cells. Together, these results suggest that in obesity, macrophages reduce epithelial cells with DNA damage, which may limit the progression of preneoplastic breast lesions, and uncovers complex macrophage function within the evolving tumor microenvironment. Understanding how obesity alters the function of macrophages during tumor formation may lead to chemoprevention options for at-risk obese women.Significance: Understanding how obesity impacts early tumor growth and response to macrophage-targeted therapies may improve therapeutics for obese patients with breast cancer and identify patient populations that would benefit from macrophagetargeted therapies.

Fibrocytes enhance mammary gland fibrosis in obesity

“…Mammary glands from HFD‐fed mice had significantly increased CD45 + CD11b + total myeloid cells compared to mammary glands from LFD‐fed mice ( p = .04, Figure 1D), confirming an increase in myeloid lineage cells that contribute to the chronic inflammatory microenvironment in the obese mammary gland. We have previously observed significantly elevated numbers of F4/80 + macrophages directly surrounding mammary ducts of HFD‐fed mice, 51 indicating that the increased numbers of macrophages are not confined to the CLS of the mammary gland.…”

Macrophages Upregulate Estrogen Receptor Expression in the Model of Obesity-Associated Breast Carcinoma

“…Taken together, the above findings suggest beneficial effect(s) of approaches aimed at manipulating Mϕ in BC, especially when taken together with previous reports attesting to Mϕ being an attractive target in mammary tumorigenesis, in general, and obesity-accelerated BC progression, in particular [ 16 , 30 , 33 , 34 , 94 ]. Yet, initial clinical studies (utilizing various agents decreasing Mϕ content) demonstrated mixed results [ 95 , 96 ]. The likely explanation for the somewhat limited benefit of the direct Mϕ targeting approach is provided by the dynamic nature and highly heterogeneous phenotypes of Mϕ [ 92 , 97 ].…”

Obesity, Type 2 Diabetes, and Cancer Risk

“…The role of macrophages in obesity-associated cancer growth is however, complex. In a pre-neoplastic model, the depletion of macrophages in diet-induced obese mice led to greater numbers of mammary epithelial cells exhibiting DNA damage and increased mammary epithelial cell progenitor activity, suggesting that macrophages potentially play a modulatory role in the early stages of cancer development ( 287 ).…”