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Estradiol Induction of Retinoic Acid Receptors in Human Breast Cancer Cells¹

Department of Medical Oncology, University of Sydney, Westmead Centre, Westmead, New South Wales 2145, Australia [S. D. R., C. L. C.]; Breast Cancer Laboratory, Tenovus Cancer Research Centre, University of Wales College of Medicine, Cardiff CF-4XX, United Kingdom [D. L. M., R. I. N.]; Department of Surgery, City Hospital, Nottingham, United Kingdom [R. W. B.]; and Cancer Biology Division [S. D. R., C. J. O., R. L. S.] and Cooperative Research Centre for Biopharmaceutical Research [S. D. R., R. L. S.], Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia

Retinoic acid inhibits proliferation and steroid receptor gene expression in human breast cancer cell lines. Retinoic acid receptors (RAR), -ß, and - are expressed in these cells and the expression of RAR is significantly greater in estrogen receptor (ER)-positive cells. This study was undertaken to determine whether the same relationship between RAR and ER gene expression was present in human breast cancers and to explore the possibility that the higher level of RAR in ER-positive cells was due to estrogen regulation of RAR gene expression. RAR and ER mRNA expression were determined by Northern blot analysis in 116 primary breast tumors; 94 (81%) tumors were ER-positive and of these 87 (93%) were also RAR-positive. The coexpression of ER and RAR was statistically significant (P = 0.0052 by x² contingency analysis). There was also a positive correlation (by linear regression analysis) between the levels of expression of ER and RAR mRNA (r² = 0.251, P = 0.001), which confirmed the relationship previously documented in breast cancer cell lines and suggested that RAR expression may be modulated in breast cancer in vivo by estrogens acting via the ER. The ability of estradiol to regulate RAR gene expression was examined in vitro using T-47D cells which had been rendered sensitive to estrogen by repeated passage in steroid-depleted medium. Estradiol increased RAR gene expression, but not that of RARß or RAR, in a concentration-dependent manner, with the effect being maximal at 10^–10 M and less marked at higher concentrations. The effect was rapid, being detectable 1 h after and maximal 6 h after treatment with 10^–10 M estradiol. Co-treatment of cells with estradiol and antiestrogens (tamoxifen or ICI 164384, 4 x 10^–7 M for 6 h) inhibited the estradiol induction of RAR gene expression, demonstrating that the effect was ER mediated. The estradiol sensitivity of the effect was underscored by the demonstration that addition of untreated serum to cells growing under steroid-depleted conditions was sufficient to induce maximal RAR gene expression. This effect was totally abolished by addition of ICI 164384. In summary, the demonstration that estradiol increased RAR mRNA levels in breast cancer cells supports the hypothesis that the correlation between RAR and ER gene expression in breast tumors and breast cancer cell lines is due to estradiol augmentation of RAR gene expression.

¹ Supported by the National Health and Medical Research Council of Australia, the Australian Government's Cooperative Research Centre Program, and the Tenovus Organisation, Wales.

² S. D. R. is the recipient of a Commonwealth of Australia Postgraduate Research Award. To whom requests for reprints should be addressed, at the Department of Medical Oncology, University of Sydney, Westmead Centre, Westmead, New South Wales 2145, Australia.

Received 6/ 1/93. Accepted 10/ 6/93.

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