Aromatase in the normal breast and breast cancer*

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Abstract

Adipose tissue and muscle constitute the larger proportion of body mass, and therefore aromatization in these tissues is the major source of circulating estrogens in postmenopausal women. Although plasma estrogen concentrations are very low, levels in breast cancers from postmenopausal patients are reported to be 10-fold higher than in plasma and normal tissue. Whereas studies on aromatase activity in the tumor suggest that estrogen may be produced locally, the significance of this contribution has been questioned. Using immunocytochemistry (ICC) to an anti-aromatase antibody, a relatively strong immunoreaction was detected in tumor epithelial cells as well as in the terminal ductal lobular units (TDLUs) of the normal breast. Aromatase expression was detected in the cytoplasm of tumor epithelial cells and the surrounding stromal cells of over 50% of tumors in a series of 19 breast cancers. In situ hybridization (ISH) to aromatase mRNA confirmed the immunocytochemical result that the epithelial cells are the primary site of estrogen synthesis in the breast and breast cancers. In the 10 tumors which showed immunoreaction to aromatase, the average aromatase activity measured in cryosections was 286.5 ± 18.6 fmol estrogen/mg protein/h (SE), whereas in nine tumors with weak aromatase immunoreaction, the enzyme activity was 154.7 ± 19.3 fmol estrogen/mg protein/h (P < 0.05) (SE). The functional significance of tumor aromatase and locally produced estrogens on the growth of tumors was suggested by the correlation between aromatase activity and proliferating cell nuclear antigen (PCNA), a marker of cell proliferation (P < 0.005). Although intratumoral aromatase activity did not correlate with steroid receptors significantly, there was a trend for estrogen receptor (ER)-positive tumors to express aromatase. In addition, proliferation ([3H]-thymidine incorporation into DNA) during histoculture, was increased by both estradiol and testosterone in tumors with high aromatase activity. Our results suggest that some tumors synthesize sufficient estrogen to stimulate their proliferation. It may thus be important to inhibit tumor aromatase as well as to reduce circulating levels of estrogen for effective breast cancer treatment.

References (46)

  • W.L. McGuire

    An update on estrogen and progesterone receptors in prognosis for primary and advanced breast cancer

  • D.L. Hemsell et al.

    Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age

    J. Clin. Endocr. Metab.

    (1974)
  • C. Longcope et al.

    Aromatization of androgens by muscle and adipose tissue in vivo

    J. Clin. Endocr. Metab.

    (1978)
  • A.A.J. van Landegham et al.

    Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue

    Cancer Res.

    (1985)
  • J.F. Dorgan et al.

    Serum estrogens and androgens and breast cancer

  • W.R. Bezwoda et al.

    Correlation of breast tumor aromatase activity and response to aromatase inhibitor with aminoglutethimide

    Oncology

    (1987)
  • W.R. Miller et al.

    The importance of local synthesis of estrogen within the breast

    Steroids

    (1988)
  • M.C. Silva et al.

    Intratumoral aromatase as a prognostic factor in human breast carcinoma

    Cancer Res.

    (1989)
  • V.H.T. James et al.

    Oestrogen uptake and metabolism in vivo

    Proc. R. Soc. Edinburgh

    (1989)
  • M.J. Reed et al.

    Concentrations of oestrone and 4-hydroxyandrostenedione in malignant and normal breast tissues

    Int. J. Cancer

    (1991)
  • Q. Lu et al.

    Expression of aromatase protein and mRNA in tumor epithelial cells and evidence of functional significance of locally produced estrogen in human breast cancers

    Endocrinology

    (1996)
  • J. Weisz et al.

    Expression of aromatase in epithelial and stromal cells in terminal lobular ductal units and in epithelial cells of cysts in normal human mammary gland

    Proc. Am. Ass. Cancer Res.

    (1995)
  • J.M. Esteban et al.

    Detection of intratumoral aromatase in breast carcinomas

    Am. J. Pathol.

    (1992)
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    *

    Proceedings of the IV International Aromatase Conference, Tahoe City, CA, U.S.A., 7–11 June 1996.

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