Obesity and breast cancer: role of inflammation and aromatase

  1. Kristy A Brown1,3
  1. 1Metabolism and Cancer Laboratory, Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia Departments of
    2Biochemistry and Molecular Biology
    3Physiology, Monash University, Clayton, Victoria 3168, Australia
  1. Correspondence should be addressed to E R Simpson; Email: evan.simpson{at}princehenrys.org
  1. Figure 1

    Diagram of the human CYP19A1 (aromatase) gene. The nine coding exons numbered II through X are shown in yellow, and the untranslated first exons are shown in red together with associated promoters. Also indicated are stimulatory factors and coregulators associated with each promoter. HBR, haeme-binding region.

  2. Figure 2

    Diagram of a breast duct, fibroblasts and adipocytes showing the principal location of aromatase in the fibroblasts. The pathways whereby oestrogen synthesised by these fibroblasts enters the duct to stimulate epithelial proliferation are indicated.

  3. Figure 3

    Diagrammatic representation of proposed epithelial–mesenchymal interactions regulating aromatase expression in the breast. Inflammatory mediators such as PGE2 produced by the tumorous epithelium stimulate the stromal fibroblasts locally to increase aromatase expression. The resulting oestrogens in turn stimulate the tumour cells to proliferate in a positive feed-on mechanism. (a) A section through breast tissue containing a large tumour (right), adipose tissue (left) and a layer of CAFs stained with aromatase antibody (Sasano H, personal communication). (b) Promoter-specific aromatase transcripts from normal breast adipose (left) and CAFs (right).

  4. Figure 4

    Expression of promoter-specific transcripts of aromatase as well as the progesterone receptor in breast tissue of overweight women, as well as those with macrophage infiltration to the adipocytes (crown-like structures, CLS)-B. PR, progesterone receptor. Adapted from Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland, with permission from AACR. Cancer Prevention Research 2011 4 329–346.

  5. Figure 5

    Current concepts of the relationship between obesity, aromatase and breast cancer emphasising the role of inflammation as a link between them. The lipid-laden adipocytes in the breasts of obese women release saturated fatty acids into the blood stream. These can activate the inflammasome complexes to initiate a cascade which results in the formation of NFκB. Saturated fatty acids also activate the toll-like receptor TLR4 which also leads to increased NFκB. The adipose tissue of obese individuals is frequently hypoxic, likely due to the fact that the lipid-engorged adipocytes can hinder the entry of blood vessels into the tissue. This results in an increase in hypoxia-inducible (HIF) 1α, which together with NFκB will stimulate the recruitment of macrophages to the lipid-laden adipocytes. These together with the adipocytes themselves will release inflammatory mediators such as PGE2, IL6 and TNFα, and these in turn will stimulate the expression of aromatase in the surrounding fibroblasts.

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