EXPRESSION OF AROMATASE PROTEIN AND MESSENGER-RIBONUCLEIC-ACID IN TUMOR EPITHELIAL-CELLS AND EVIDENCE OF FUNCTIONAL-SIGNIFICANCE OF LOCALLYPRODUCED ESTROGEN IN HUMAN BREAST CANCERS

The expression of aromatase by breast cancer cells and the role of loc ally produced estrogen in the stimulation of tumor growth has been con troversial. The present study was performed to determine the site of a romatization in human breast cancers, using both immunocytochemistry a nd in situ hybridization. The functional significance of locally produ ced estrogens on growth of the tumor was addressed by measuring aromat ase activity and a marker of proliferation (PCNA score). In addition, histocultures of some tumors were carried out to investigate whether t estosterone aromatization could stimulate tumor proliferation. Of the 19 tumors investigated, 10 (52.6%) showed significant immunoreactivity to antiaromatase antibody in the cytoplasm of tumor epithelial cells and in surrounding stromal cells. The presence of aromatase mRNA detec ted by ISH was also located in tumor epithelial cells and stromal cell , and the pattern of expression was the same as with immunocytochemist ry. In the ten tumors that showed immunoreaction to aromatase, the ave rage aromatase activity measured in cryosections was 286.5 +/- 18.6 (S E) fmol estrogen/mg protein . h, whereas in nine tumors with weak arom atase immunoreaction, the enzyme activity was 154.7 +/- 19.3 (SE) fmol estrogen/mg protein . h (P < 0.05). The mean PCNA score was 33.8 +/- 5.1 (SE)% in strongly stained tumors and 20.8 +/- 2.0 (SE)% in weakly stained tumors (P < 0.05). Aromatase activity level and PCNA score wer e significantly correlated. In histoculture of four tumors, estradiol increased the incorporation of [H-3]-thymidine into DNA. In two of the se tumors, aromatase activity was high and [H-3]-thymidine incorporati on into DNA was also stimulated by testosterone. In the other two tumo rs that had low aromatase activity, no such stimulation occurred with testosterone. The results indicate that aromatase is expressed mainly in tumor epithelial cells and that sufficient amounts of estrogen are synthesized by the tumor to produce a proliferative response. It is co ncluded that estrogen synthesis by cancer cells could play a important role in promoting growth in a significant proportion of breast tumors .