Accession Number : ADA299268
Title : Hormone Resistance and Progesterone Receptors in Breast Cancer.
Descriptive Note : Annual rept.,
Corporate Author : COLORADO UNIV HEALTH SCIENCES CENTER DENVER
Personal Author(s) : Horwitz, Kathryn B.
PDF Url : ADA299268
Report Date : 06 JUL 1995
Pagination or Media Count : 10
Abstract : Women develop breast cancer because they have ovaries. Analyses of factors involved in breast cancer induction, growth, and treatment has therefore focused on estradiol and progesterone; particularly on estradiol. The latter is a growth promoter, and blockade of estradiol at the tumor with the antiestrogen tamoxifen is a major thrust of current endocrine therapies. But is estradiol the only ovarian hormone with an impact on breast cancer development and proliferation? Progesterone has a proliferative effect in the epithelium of the normal breast, and progestin agonists at physiological doses promote the growth of experimental mammary cancers. Progesterone antagonists inhibit the growth of breast cancer (1-3). In human breast cancers there are two, naturally occurring, PR isoforms: the 769 amino acid A-receptors; and the 933 amino acid B-receptors, that have a 164 amino acid extension at the N-terminus -- which we call the B-upstream segment, or BUS. Downstream of BUS, A- and B- receptors are identical. The two receptors can form homo- and heterodimers, leading to three dimeric species (A:A, A:B, B:B) that bind DNA (1, and references therein). Our preliminary data show that the A- and B-isoforms are functionally dissimilar when occupied by agonists. Additional data show that progesterone antagonists can either inhibit or stimulate transcription, depending on the receptor isoform, the promoter of the gene being regulated, and the modulatory influence of other signalling pathways, particularly of cAMP (4,5). We postulate that breast cancers become "resistant" to hormone therapy because antagonists acquire inappropriate, agonist-like, effects. The clinical consequences of such a functional switch are grave.
Descriptors : *HORMONES, *GROWTH(GENERAL), *AMINO ACIDS, *CANCER, *MAMMARY GLANDS, *OVARIES, EPITHELIUM, HUMANS, MOLECULES, NEOPLASMS, DEOXYRIBONUCLEIC ACIDS, DOSAGE, THERAPY, PHYSIOLOGY, WOMEN, INDUCTION SYSTEMS, PHARMACOLOGICAL ANTAGONISTS, RESISTANCE(BIOLOGY), PROGESTERONE.
Subject Categories : Anatomy and Physiology
Medicine and Medical Research
Distribution Statement : APPROVED FOR PUBLIC RELEASE