Steroid hormone receptors as targets for the therapy of breast and prostate cancer--recent advances, mechanisms of resistance, and new approaches.
Surgical ovariectomy and orchiectomy, first proposed over a century ago, are effective in breast and prostate cancer therapy, respectively. Later, the discovery of steroid hormones and their nuclear receptors led to the concept that inhibition of steroid receptor function by an antagonist prevents tumour growth. While the first anti-hormones, cyproteroneacetate (CPA) and tamoxifen were found accidentally, deeper understanding of nuclear receptors as transcription factors enabled more rational, structure-activity based drug discovery. Results from a drug-finding program on pure anti-estrogens will be reported. These new steroidal anti-estrogens are highly active, pure ER-antagonists that lead to an efficient degradation of the estrogen receptor alpha (ERalpha) protein without any agonistic activity. Data obtained in preclinical tumour models in mice and rats showed a high potency in growth inhibition of ERalpha-positive breast cancer. In parallel, by comparing three independently generated anti-estrogen-resistant breast cancer cell lines, it was our intention to gain insight into the mechanisms of endocrine resistance which will allow to define new approaches for the treatment of endocrine-resistant breast cancer. Candidate proteins potentially involved in mechanisms of anti-estrogen-resistant growth of breast cancer cell lines were analyzed. ERalpha and progesterone receptor (PR) expressions were lost on the protein level in all three anti-estrogen-resistant cell lines, whereas binding of epidermal growth factor (EGF) and protein expression of epidermal growth factor receptor (EGFR) were increased. Loss of ERalpha expression may be linked to the acquisition of anti-estrogen resistance and enhanced expression of the EGFR and of members of the S100 family of Ca2+-binding proteins may contribute to the outgrowth of resistant cells. Furthermore, we describe the pharmacological development of a novel, highly potent progesterone receptor antagonist. In rat mammary tumour models, treatment with the PR antagonist completely suppressed the growth of established tumours and prevented the development of breast tumours. Advanced prostate cancer is effectively treated by androgen ablation. However, this therapy becomes inefficient although the androgen receptor (AR) is still functionally expressed. One novel strategy for the treatment of advanced prostate cancer could be the selective inhibition of AR protein expression by anti-sense oligonucleotides or small interfering RNA (siRNA) molecules. Down-regulation of the human AR caused significant inhibition of LNCaP prostate cancer growth in vivo. Taken together, many promising alternatives for endocrine therapy of breast and prostate cancer are arising.
Hoffmann
J
J
Research Laboratories of Schering AG, Müller Str. 178, 13342 Berlin, Germany. jens.hoffman@schering.de
Sommer
A
A
D059002:Androgen Receptor Antagonists; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors*
D059002:Androgen Receptor Antagonists; D020847:Estrogen Receptor Modulators; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid