This thesis comprises 61 papers which describe work undertaken between 1972 and
1985. The research was performed in order to obtain basic information on the
environment and the biochemical processes existing within the female breast. It
was thereby hoped to achieve a better understanding of events which occur during
the development of breast disease, particularly breast cancer.
Hormones are involved not only in the natural development of normal breast but
also in the aetiology of many breast abnormalities and, most importantly, in the
continued growth of a proportion of breast cancers. A major aspect of the research
described in this thesis is concerned with the measurement of steroid hormones,
their metabolism and receptors in the breast, its tumours and secretions.
Additionally studies have been performed to assess the significance of other
markers of tumour behaviour and to determine whether agents such as LHRH analogues
have direct effects within the breast.
The potential of the breast to modify its own hormonal environment has been
investigated by performing in vitro incubations with steroid precursors. Pathways
leading to both active androgens and oestrogens have been identified. Biosynthesis
of 5 reduced androgens occurs in all types of breast tissue but is particularly
associated with apocrine differentiation. The production of oestrogen or
"aromatization" was detected in a proportion of breast cancers but not in non-malignant
tissue. The significance of tumour aromatase is controversial but it may be
important in oestrogen-dependent cancers growing in post-menopausal women who have
low circulating levels of oestrogen.
In order to estimate levels of androgen precursors within the breast, measurements
of DHA sulphate have been made in breast secretions obtained by nipple aspiration
and breast cyst fluids. Remarkably high, but variable, concentrations have been
detected. Further investigations of the composition of such breast fluids have shown
them to have a distinctive composition in terms of ionic content, major types of
immunoglobulins and concentrations of plasma-, platelet-associated and other proteins.
Cyst fluids may be subdivided into two major populations which are lined by different
epithelium and have a differing natural history.
Several series of breast cancers have been analysed for either androgen receptors,
progestogen receptors, cyclic AMP binding proteins, prostaglandins or expression of
lectin binding. These have been suggested to be markers of metastatic potential or
hormone-responsiveness. Inter-relationships have been made with oestrogen receptors
and other tumour/patient characteristics but assessment of clinical value awaits
The possibility that polypeptide hormones have direct actions on the breast was
investigated by culturing breast cancer cells with LHRH and its analogues. Marked
inhibitory effects which appear to be mediated by a specific recognition mechanism have
been demonstrated. These findings are reviewed in terms of their significance to the
management of patients with breast disease.
SECTION A STEROID METABOLISM BV THE HUMAN BREAST AND ITS TUMOURS
1. Miller W R, McDonald D, Forrest A P M and Shivas A A (1 973)
Metabolism of androgens by human breast tissue. The Lancet
2. Miller W R, McDonald D and Forrest A P M (1 973)
Steroidogenesis in human breast cancer, benign breast disease
and normal breast tissue. Biochemical Society Transactions
3. Miller W R, McDonald D, MacFadyen I, Roberts M M and Forrest A
P M (1974) Androgen metabolism in gynaecomastic breast
tissue. Clinical Endocrinology 3.; 123-130.
4. Miller W R and Forrest A P M (1974) Oestradiol synthesis by
a human breast carcinoma. The Lancet ii:866-868.
5. Miller W R and Forrest A P M (1 976) Oestradiol synthesis
from C.|q steroids by human breast cancers. Br J Cancer
6. Miller ¥ R, Shivas A A and Forrest A P M (1978) Factors
affecting testosterone metabolism by human breast tissues.
Clinical Oncology l;77-85.
7. Miller W R (1981) Inhibition of aromatization by
aminoglutethimide in breast cancers - clinical relevance. In
"Aminoglutethimide. An alternative endocrine therapy for
breast carcinoma" ed. R W Elsdon-Dew, I M Jackson and G F B
Birdwood. Royal Society of Medicine International Congress
and Symposium Series No. 53. Academic Press Inc (London) Ltd.
8. Miller W R, Hawkins R A and Forrest A P M (1981) Steroid
metabolism and oestrogen receptors in human breast carcinomas.
Europ J Cancer (Clin Oncology) 17:913-917.
9. Mason R C, Burns D A, Miller W R, Hawkins R A and Forrest A P
M (1981) Tumour steroid synthesis and oestrogen receptor
status in breast cancer patients. Breast Cancer Treatment &
10. Miller W R, Hawkins R A and Forrest A P M (1 982)
Significance of aromatase activity in human breast cancer.
Cancer Research 42:3365-3368.
11. Miller W R Aromatase activity and breast cancer. Turkey
National Cancer Prevention Association Booklet.
12. Miller W R and Forrest A P M (1 978) In vitro effects of
oestradiol on testosterone metabolism by human breast cancers.
European J Cancer 14:865-867.
13. Mason R C, Miller W R, Hawkins R A, Brown M S and Forrest A P
M (1983) Effects of drugs associated with
hyperprolactinaemia and plasma steroids and on steroid
receptors and metabolism in human breast cancer. Breast
Cancer Research and Treatment 3;331-338.
14. Miller W R, Telford J, Dixon J M and Shivas A A (1985)
Androgen metabolism and apocrine differentiation in human
breast cancer. Breast Cancer: Research and Treatment 3; 67-
15. Miller W R (1986) Steroid metabolism in breast
cancer. In "Breast cancer: Treatment and Progress" Ed. B A
Stoll. Published Blackwell Scientific Publications,
16. MillerW R (1986) Steroid metabolism in breast cancer.
Reviews on Endocrine-Related Cancer. 23;23-30.
SECTION B. STEROID METABOLISM BY (A) RAT MAMMARY TUMOURS AND (B)
OTHER HUMAN TISSUES
17. Miller W R, Forrest A P M and Hamilton T (1974) Steroid
metabolism by human breast and rat mammary carcinoma.
18. Miller W R (1976) Hyperprolactinaemia and steroid metabolism
by rat mammary adenocarcinoma. Cancer Research 36.5336-338.
19. Miller W R, Buchan R and Forrest A P M (1974) Effects of
prolactin upon C₁₉ steroid metabolism by rat mammary
carcinoma. Biochemical Society Transactions 2.5312-314,
20. Buchan P, Fraser A T and Miller W R (1976) The effect of
perphenazine treatment on testosterone metabolism by
established rat mammary carcoinomas. Biochem Soc Transact
21. Buchan P and Miller W R (1978) Perphenazine and testosterone
metabolism by mammary tumours in oophorectomised rats.
Biochem Soc Transact 6;133-134.
22. Miller W R (1976) Hormone status and testosterone metabolism
of DMBA induced rat mammary carcinomas. Br J Cancer 34:296-
23. Miller W R (1976) In vitro effects of oestrogen on 5α
reduction of testosterone in hormone dependent rat mammary
carcinomata. Br J Cancer 33:474-477.
24. Miller W R (1976) in vitro effects of prolactin upon
testosterone metabolism by rat mammary carcinomas. European
J Cancer 18:679-682.
25. Miller W R and Telford J (1 975) The effect of oestrogen on
steroid metabolism by rat mammary carcinomas. Bui Soc Int
26. Miller W R (1980) The effects of serial passage on the
endocrine response and steroid metabolism of a rat
transplantable mammary carcinoma. Br J Cancer J(2.;326-330.
27. Miller W R, Stewart R and Hawkins R A (1979) Hormonal status
and steroid metabolism in two transplantable rat mammary
Br J Cancer 29.;200-204.
28. Miller W R, Shivas A A and Forrest A P M (1974) Steroid
metabolism by human normal thyroid, nodular goitre and thyroid
cancer. Br J Cancer 2Q.; 284-287.
29. Miller W R, Shivas A A and Forrest A P M (1976) Steroid
interconversions by metastatic deposits of a human
bronchogenic carcinoma. Clinical Oncology 2; 127-130.
SEQTIQN C - URINARY STEROIDS IN PATIENTS WITH BREAST DISEASE
30. Miller W R, Hamilton T, Champion H R, Wallace I W J, Forrest A
P M, Prescott R J, Cameron E H D and Griffiths K (1975)
Urinary aetiocholanolone in patients with early breast cancer
from South East Scotland and South Wales. Br J Cancer
31. Prescott R J, Miller W R and Hamilton T (1978) Urinary
aetiocholanolone and prognosis in early carcinoma of the
breast. J Surgical Oncology 10:847-851.
SECTION D - COMPOSITION OF BREAST FLUIDS
32. Miller W R, Humeniuk V and Kelly R W (1980)
Dehydroepiandrosterone sulphate in breast secretions. J
Steroid Biochem 18:145-1 51.
33. Miller W R, Humeniuk V and Forrest A P M (1981) Factors
affecting dehydroepiandrosterone sulphate levels in human
breast secretions. Breast Cancer Research & Treatment 1;267-
34. Yap P L, Miller W R, Humeniuk V, Pryde E A D, Mirtle C L and
McClelland D B L (1981) Milk protein concentrations in the
mammary sections of non-lactating women. J Reprod Immunol
35. Miller W R, Roberts M M, Creel R J, Yap P L, Kelly R W and
Forrest A P M (1982) Androgen conjugates in human breast
cyst fluids. J.Nat. Can. Inst. 1055-1058.
36. Miller W R and Forrest A P M (1 983) Androgen conjugates in
human breast secretions and cyst fluids. In "Endocrinology
of Cystic Breast Disease" Ed. A Angeli et al. Published by
Raven Press, New York pp. 77-84.
37. Miller W R, Dixon J M, Scott W N and Forrest A P M (1983)
Classification of human breast cysts according to electrolyte
and androgen conjugate composition. Clin Oncology 9;227-232.
38. Dixon J M, Miller W R, Scott W N and Forrest A P M (1983)
The morphological basis of human breast cyst populations. Br
J Surg 70:604-606.
39. Dixon J M and Miller W R (1984) Human Breast cystic disease.
Breast News 1;6—9.
40. Dixon J M, Scott W N and Miller W R (1985) Natural history of
cystic disease: the importance of cyst type. Br J Surg
41. Dixon J M, Lumsden A B and Miller W R (1 985) The
relationship of cyst type to risk factors for breast cancer
and the subsequent development of breast cancer in patients
with breast cystic disease. Europ J Cancer 21:1Q47-1050.
42. Dixon J M and Miller VI R (1984) The pH of human breast cyst
fluids. Clinical Oncology 10:221-224.
43. Yap P C, Miller W R, Roberts M M, Creel R J, Freedman B, Pryde
E A D and McClelland D B L (1984) Protein concentrations in
fluid from gross cystic disease of the breast. Clinical
Oncology 1 0:35-43.
44. Miller W R and Dixon J M (1986) Hormonal correlates of
apocrine secretion in the breast. Annals of the New York
Academy of Science 464:275-287.
45. Miller W R and Dawes J (1985) Platelet-associated proteins
in human breast cyst fluids. Clin Chim Acta 192:37-42.
46. Dixon J M, Scott W N and Miller W R (1 985) An analysis of
the content and morphology of human breast microcysts. Europ
J of Surg Oncol H; 151-154.
SECTION E = MARKERS OF TUMOUR BEHAVIOUR
47. Hawkins R A, Hill A, Freedman B, Killen E, Buchan P, Miller W
R and Forrest A P M (1977) Oestrogen receptor activity and
endocrine status in DMBA induced rat mammary tumours.
European J Cancer 13.5223-228.
48. Hawkins R A, Hill A, Freedman B, Killen E and Miller W R
(1978) Oestrogen receptor activity in transplantable ovary
independent mammary tumours of the rat. Europ J Cancer
49. Hawkins R A, Tesdale A, Freedman B, Telford J and Miller W R
(1981) Progestogen and oestrogen receptor activity in ovary
dependent and ovary independent tumours of the rat. Europ J
Cancer 5.558 5-587-
50. Mason R C, Steele R J C, Hawkins R A, Miller W R and Forrest A
P M (1982) Cellularity and the quantification of oestrogen
receptors. Breast Cancer Treatment and Research 2.5239-242.
51. Miller W R, Telford J and Hawkins R A (1 983) Binding of 3h
methyltrienolone (R1881) by human breast cancers. Europ J
Cancer (Clin Oncology) 12.5 1473-1478.
52. Miller W R, Telford J, Dixon J M and Hawkins R A (1 985)
Androgen receptor activity in human breast cancer and its
relationship with oestrogen and progestogen activity. Europ
J Cancer 21;539-542.
53. Watson DMA, Kelly R W, Hawkins R A and Miller W R (1984)
Prostaglandins in human mammary cancer. Br J Cancer 4Q45Q-
54. Miller W R, Senbanjo R 0, Telford J and Watson DMA (1 985)
Cyclic AMP binding proteins in human breast cancer. Br J
55. Miller W R, Sturgeon C M and Walker R A (1 983) Carcino
embryonic antigen (CEA) in explants of human breast cancer:
comparison of immuno histochemical detection and release
during short-term culture. Br J Cancer 47:429-432.
56. Zangerle P F, Collette J, Hendricks J C, Miller W R and
Franchimont P (1982) Milk proteins and breast cancer. In
"Markers for Diagnosis and Monitoring of Human Cancer" Ed. M I
Colnaghi, G I Buragge, Ghione M. Academic Press, London and
New York. pp 35-49.
57. Walker R A, Hawkins R A and Miller W R (1985) Lectin binding
and steroid receptors in human breast carcinomas. J Pathol 147; 103-106.
SECTION F - DIRECT EFFECTS OF POLYPEPTIDES .ON BREAST CANCER CELLS
58. Miller W R, Scott W N, Morris R, Fraser H M and Sharpe R M
(1 985) Growth of human breast cancer cells inhibited by a
luteinizing hormone-releasing hormone agonist. Nature
59. Miller W R, Scott W N, Morris R, Fraser H M and Sharpe R M
(1986) Direct effects of LHRH and agonists on human breast
cancer cells. "Neuroendocrine Molecular Biology". Ed. G
Fink, A J Harmar, K W McKerns. Plenum Press: New York and
SECTION G - REVIEWS
60. Forrest A P M and Miller W R (1985) Hormones and female
breast cancer: clinical relevance. In "Accomplishments in
Cancer Research" General Motors Publication Ed J G Fortner
and J E Rhoads.Pub. J B Lippincott Co. Philadelphia pp 134-
61. Miller W R and Anderson, T A Oestrogens, progestogens and
the breast. In "The Menopause". Eds M I Whitehead and J
Studd. Pub.Blackwell Scientific Press (in press).