Mammary Adipose Tissue and Breast Cancer

It is known that inflammation can promote tumorigenesis. There is compelling evidence indicating that both normal mammary gland development and breast cancer growth depend, in part, on microenvironment, of which adipose tissue is a key component (ref. 28 and references therein). Interestingly, the mammary gland microenvironment during postlactational involution shares similarities with inflammation, which may be promotional for breast cancer development associated with pregnancy (54). Recently, an elegant study by Celis et al. (28) provided the most extensive proteomic analysis of the mammary adipose secretome in high-risk breast cancer patients.

Adipose fibroblasts are another important cellular component of breast cancer microenvironment. These cells, being bona fide steroidogenic cells, are one of the major extragonadal sources of estrogen secretion. Estrogen synthesis is mediated by the enzyme aromatase cytochrome P450 (P450arom), which converts androgens to estrogens (55). In breast cancer, one of the most aggressive human cancers, intratumoral proliferation of breast adipose fibroblasts is accompanied by increased P450arom expression by these cells, leading to proliferation of breast epithelial cells (56). Notably, breast cancer commonly associates with a prominent immune, especially mast cell, response (57-59). TNF-a and IL-6, which may potentially derive from both adipose cells and mast cells, upregulate aromatase expression (60). Further, mast cell-secreted tryptase is a potent stimulator of fibroblast proliferation (61), and adipocytes also produce tryptase (12).

A novel piece to the puzzle of breast cancer is that NGF, a molecule known to be produced by adipocytes (5,27,28,43,49) and mast cells (34,62), stimulates breast cancer cell proliferation (63,64). Importantly, the antiestrogen drug tamoxifen inhibits NGF-mediated breast cancer cell proliferation through inhibition of the Trk-A receptor (63). These data suggest a novel, NGF-mediated mechanism in the action of an old drug, tamoxifen, in breast cancer pharmacotherapy. Together these findings open possibilities for an adipose NGF-/mast cell-oriented therapy of breast cancer (1), and pressingly call for studies on pharmacology of this neoplastic disorder.

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