
How best, to express oestrogen receptor activity

Sir

With reference to the recent editorial by RA Hawkins (1996), I feel
compelled to take issue with the opening sentence and the rather
provocative statement 'The oestrogen receptor (ER), discovered
around 1960 ...' and the references cited therein. Whatever the
controversy surrounding methods of assay and the clinical signifi-
cance of ER as a prognostic and predictive factor, its nascent
details are worthy of clarification.

The physiological basis for responses to early forms of ablative
endocrine therapies was unknown at the time of their clinical intro-
duction (Schinzinger, 1889; Beatson, 1896). Oestrogens were only
isolated in crystalline form in 1936 from sows' ovaries by
MacCorquadale and co-workers (1936). Despite the isolation of
oestrogens and animal data implicating these substances in both
initiation and promotion of mammary tumours in rodents (Eisen,
1932; Lacassagne, 1932), evidence for a direct role in normal
breast function and development of mammary neoplasia was
lacking. Glascock and Hoekstra published a seminal paper in 1959
on the selective accumulation of radiolabelled synthetic oestrogens
in target organs that respond to these hormones. A tritiated
oestrogen derivative of high specific activity selectively localized
in the mammary glands, uterus, vagina and pituitary glands
of immature goats and sheep. This was important corroborative
data linking oestrogen with normal breast physiology, and subse-
quently the selective uptake of radiolabelled systemic oestradiol by
7,12-dimethylbenzanthracene (DMBA)-induced rat mammary
tumours was demonstrated (King, 1965; Mobbs, 1966; Terenius,

1968). However, although the existence of putative oestrogen
receptors was postulated they were not identified in these experi-
ments.

The formal discovery of the oestrogen receptor (ER) came in
the mid to late 1960s by groups led by Gorski and Jensen (Toft and
Gorski, 1966; Jensen et al, 1968). These workers carried out
further experiments that consolidated understanding of oestrogen-
stimulated growth. Radiolabelled oestradiol incubated with uterine
tissue of immature rats was bound to cytosolic and nuclear frac-
tions. The oestradiol in the cytosol was associated with a specific
oestrogen-binding protein that was undetectable in the nuclear
fraction. These findings led to formulation of an early model for
oestrogen-mediated events in which oestrogen interacted directly
with target cells via cytoplasmic receptors. Subsequent transloca-
tion of the ligand-receptor complex to the nucleus was followed
by interaction with DNA and modulation of gene transcription.
The presence or absence of ER was consistent with data showing
that uptake of tritiated oestradiol by breast tumour samples was
essentially 'all or none' - tumours accumulated oestradiol either
significantly or ubrewer@example.net. This preliminary model has now been
refined and, in particular, evidence now suggests that native forms
of the unoccupied ER do reside within the nucleus. The precise
conditions that determine nuclear localization remain to be eluci-
dated (Jensen, 1991).

These observations have heralded the modern era of endocrine
therapy in which the clinical response of advanced breast cancers
could be predicted from the ER content of metastatic lesions
(McGuire, 1975) and later of primary tumours (Campbell, 1981).

British Journal of Cancer (1997) 76(3), 416-419                                       0 Cancer Research Campaign 1997

Letters to the Editor 419

Science is an evolutionary process, and contemporary scientific
debate should not eclipse nor distort historical fact.
JR Benson,

Department of Surgery Westminster Ward,

Level 3, Chelsea and Westminster Hospital,
369 Fulham Road, London SWIO 9NH, UK

REFERENCES

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and Haybittle JL (1981) Quantitative oestradiol receptor values in primary
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Eisen MJ (1932) The occurrence of benign and malignant mammary lesions in rats

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C) Cancer Research Campaign 1997                                          British Journal of Cancer (1997) 76(3), 416-419


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