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Breast Cancer and the Role of Cytokines in Regulating Estrogen Synthesis: An Emerging Hypothesis

Unit of Metabolic Medicine, Imperial College School of Medicine at St. Mary’s, London W2 1PG, United Kingdom

I. Introduction

II. Peripheral Estrogen Synthesis and Blood and Tissue Estrogens in Breast Cancer

A. Peripheral estrogen synthesis

B. Aromatase

C. Estrone sulfatase

D. E2DH

E. Origins of breast tumor estrogens

III. Influence of Breast Tumor Location on Enzyme Activities in Adjacent Tissues

IV. Proposed Model for the Regulation of Estrogen Synthesis in Breast Tumors

V. Evidence in Support of Proposed Model of Cytokine Regulation of Estrogen Synthesis

A. Identification of factors that stimulate estrogen synthesis

B. Potentiation of cytokine stimulation of estrogen synthesis

VI. The Role of Soluble Cytokine Receptors in Cytokine Action

A. Mechanism of cytokine action

B. Regulation of gp80 and gp130

C. Regulation of IL-6 sR shedding

VII. Origin of Estrogen-Stimulating Factors in Breast Tumors

A. The role of cells of the immune system

B. Macrophages and lymphocytes in breast tumors

VIII. Regulation of Lymphocyte Cytokine Production

A. Th1 and Th2-helper cells

B. Dehydroepiandrosterone (DHA) and glucocorticoids

IX. Clinical Observations Explained by Proposed Model of Cytokine Regulation of Estrogen Synthesis

A. Septic shock

B. The effect of aging on peripheral estrogen synthesis

C. The effect of weight on peripheral aromatase activity

D. The discriminant function test

E. Stress and breast cancer

F. Immunosuppression and breast cancer risk

G. Failure of glucocorticoids to stimulate aromatase activity in vivo

X. Summary and Future Perspectives

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