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Steroid Hormone Receptors and Their Clinical Significance in Cancer J Clin Pathol: First Published As 10.1136/Jcp.48.10.890 on 1 October 1995

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Steroid Hormone Receptors and Their Clinical Significance in Cancer J Clin Pathol: First Published As 10.1136/Jcp.48.10.890 on 1 October 1995 89080 Clin Pathol 1995;48:890-895 Steroid hormone receptors and their clinical significance in cancer J Clin Pathol: first published as 10.1136/jcp.48.10.890 on 1 October 1995. Downloaded from R I Nicholson, R A McClelland, J M W Gee Introduction (aE, ,B and y) and so called "orphan" receptors,'0 Although all cells within the body are exposed which do not have recognised physiological to steroid hormones, their physiological actions ligands as yet (including HNF-4,'5 COUP,'6 are limited to those tissues which contain in- Rev-erb A-alpha,'7 Nur77,'8 NGFI-B,'9 TR3,2. tracellular binding proteins, termed receptors. retinoid X receptor,2' P-450 inducers," These proteins specifically bind the individual and the DHR3/MHR3 proteins22), show classes of steroid hormones with high affinity marked conservation of structure and contain and transmit the steroid signal to sensitive genes various functional domains, including those for located throughout the chromatin. The type of ligand and DNA binding.2324 In each instance response subsequently induced is dependent the steroid receptors act as ligand inducible on both the developmental stage and differ- nuclear transcription factors, with interactions entiation status of the target tissue, but may between activated receptors and hormone re- involve the control of such diverse end points sponse elements (HRE) on the DNA directly as cell proliferation, cell death, secretory ac- modifying gene expression. 1 2125 Although tivity, and cellular mobility. Importantly, the some differences exist with respect to the or- ability of steroid hormones to influence these ganisation and initial cellular localisation of characteristics is retained in many disease the individual classes ofsteroid hormone recep- states, notably in certain cancers originating tors, 2 they all ultimately act to stimulate or in steroid hormone sensitive tissues including repress mRNA production from sensitive carcinomas of the breast,' genital tract,23 gas- genes, leading to changes in protein synthesis trointestinaI tract,4 pancreas,5 lung,6 and also and finally cellular function.23-25 However, it intracranial tumours.7 This has been harnessed has become increasingly evident that steroid therapeutically, with drugs which modify the hormone receptors represent only part of the cellular levels or actions of steroid hormones transcriptional apparatus involved in the being commonly used in the treatment of regulation ofresponsive genes and that they act breast, endometrial and prostate cancer.89 in concert with other inducers or suppressors of http://jcp.bmj.com/ These tumours frequently retain steroid hor- gene expression. 10 26 Thus, hormonally directed mone receptors and their measurement is cur- genes can show responsiveness to peptide rently used diagnostically in several centres to growth factors. This is exemplified by the oes- identify potential endocrine responsiveness. trogen regulated gene pS2 (pNR2) which has As steroid sensitive cancers are relatively been shown to be sensitive to the growth factors common and as cellular transitions associated transforming growth factor cz (TGFoc), epi- with the loss of their hormone sensitivity in- dermal growth factor and also insulin-like on September 26, 2021 by guest. Protected copyright. variably worsen the prognosis for a patient, growth factor I.27 A further example is seen considerable effort has been afforded to their with PR, traditionally an oestrogen regulated study. The examination of steroid hormone protein, which can also be activated through receptors is pivotal to our understanding of dopaminergic and adrenergic signalling mech- endocrine sensitivity and therefore the current anisms.28 Such interactions raise interesting article attempts to summarise our present questions concerning the role of cross-talk be- knowledge ofthese proteins specifically in those tween steroid hormone receptors and other areas of cancer biology which we hope are of signalling pathways in the regulation of tran- particular interest to the pathologist. scriptional efficiency, constitutive action of the receptor and acquisition of endocrine re- sistance. A knowledge of such pathways may Molecular aspects of steroid hormone provide previously unrecognised opportunities receptors for tumour therapy.'° Breast Cancer The past decade has seen a remarkable increase Laboratory, in our knowledge of the structure and function Tenovus Cancer ofsteroid hormone receptors. This has occurred Methods of detection Research Centre, University of Wales through the isolation and sequence analysis of The observation that hormone sensitive tissues College of Medicine, recombinant DNA clones for the individual were able to take up and retain radiolabelled Cardiff CF4 4XX receptors. It is now established that the receptor steroids against a concentration gradient of the R I Nicholson proteins from each of the five classes of steroid steroid26 lead to the initial discovery of steroid R A McClelland J M W Gee hormones, notably oestrogens (ER)'0 and hormone receptors. This property was sub- progestins (PR),'0 androgens (AR), gluco- sequently exploited in "test tube" biochemical Correspondence to: 12 J M W Gee. corticoids (GR)," and mineralocorticoids, as assays, notably dextran coated charcoal (DCC) Accepted for publication well as the receptors for thyroid hormone," adsorption ligand binding assays (LBA' 26), 18 January 1995 1,25-dihydroxy vitamin D3 (VDR),'4 retinoids generating information on the concentration of Steroid hormone receptors and their clinical significance in cancer 891 steroid hormone receptors within solubilised Glasgow), providing new workers with vital tissue extracts, together with their binding information regarding steroid receptor QA affinity constants. Unfortunately, the ease of materials, QA schemes as well as a reference J Clin Pathol: first published as 10.1136/jcp.48.10.890 on 1 October 1995. Downloaded from performing these assays and also their sub- directory of expert laboratories currently en- sequent clinical value varies between tumour gaged in such assays. types and surgical procedures used. Thus, while Early immunocytochemical studies using breast and endometrial cancer samples are rel- antibodies directed against ER (for example, atively accessible enabling valuable data to be H222 antibody, available in the ER-ICA kit" readily obtained, it is often essential to remove from Abbott Diagnostics, North Chicago, Il- prostate tumour specimens by transurethral linois, USA) showed that the protein is localised sectioning, a procedure which generates el- exclusively within the epithelial cell nuclei in evated temperatures and consequently is po- suitably fixed cryosections" (that is, frozen tentially damaging to any receptor proteins.26 specimens stored at - 700C, sectioned and Furthermore, the assays are also influenced by fixed for 10 to 15 minutes in 3-7% form- both the cellularity of the cancer and the con- aldehyde/phosphate buffered saline at room tent and associated steroid hormone receptor temperature; post-fixed in methanol (five min- status ofnormal or benign tissue. These factors utes) and acetone (three minutes) at - 200C) may contribute towards falsely negative or of normal and cancerous genital tract, breast, positive receptor results. pituitary, and liver. This observation was at More recently developed methodologies rely odds with the previously held view of this re- on direct antigen recognition rather than ster- ceptor as a cytosolic protein which was sub- oid binding activity, utilising monoclonal sequently translocated to the nucleus following antibodies29 specific for the various steroid re- its activation by oestrogens. It is now believed ceptors in both enzyme immunoassays (for ex- that, with the exception of glucocorticoid re- ample, oestrogen receptor enzyme immuno- ceptors, each class of steroid hormone receptor assay (ER-EIA)"0) and also immunocyto- resides predominantly in the nuclei of steroid chemistry (for example, oestrogen receptor sensitive cells.' immunocytochemical assay (ER-ICA) 2631). Using such antibodies, ER (H222 and 1D5 The value of the latter technique lies in its (Dako, High Wycombe, UK)) and PR may relevance to histological sections and thus the now also be reliably localised in 10% buffered procedure has numerous advantages for the formalin fixed (exposed to formalin for no pathologist. Steroid receptors can be directly longer than 24 hours as prolonged fixation visualised by a colour reaction within individual results both in decreased receptor immuno- cell types. This is not possible using bio- reactivity and in the appearance ofnon-specific chemical methods, which require that tissues cytoplasmic staining), paraffin wax embedded should be homogenised before being assayed, material following the re-exposure of masked with an associated loss ofinformation regarding antigenic determinants by controlled protease heterogeneity ofreceptor expression in normal, digestion of the tissue sections'6 or microwave http://jcp.bmj.com/ benign and malignant components of the treatment.'7 These procedures maintain ex- tumour.26 Immunohistochemical assays can cellent tissue preservation, and thus accurate also be applied to biopsied or cytological ma- receptor determinations can be made in the terial' and thus have the ability to generate invasive component of archival tumours, as accurate results on low cellular tumours. Fur- well as within small, early cancers which are thermore, the technique allows several different usually processed entirely
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