The role of oestrogens and progestagens in the epidemiology and prevention of breast cancer

It has been demonstrated that in humans certain factors such as early menarche, late pregnancy, and nulliparity are associated with a higher risk of developing breast cancer, while early pregnancy acts as a protective factor. Induction of mammary cancer in rats by administration of the chemical carcinogen 7, 12-dimethylbenz(a)anthracene reveals that the same factors influencing human breast cancer risk also affect the susceptibility of the rat mammary gland to the chemical carcinogen. Nulliparous rats and rats undergoing pregnancy interruption are more susceptible to developing carcinomas. This fact has been attributed to the incomplete differentiation of the gland at the time of carcinogen administration. Parous rats are resistant to the carcinogenic effect of DMBA, which is explained by the complete development of the gland attained during pregnancy and lactation. This development is manifested by the differentiation of terminal end buds into secretory units, which have a smaller proliferative compartment; the epithelial cells of these secretory units have a longer cell cycle, less avidity for binding DMBA, and possess a more efficient DNA excision repair capacity.

Differentiation of the mammary gland and susceptibility to carcinogenesis

Estimating steroid oestrogen inputs into activated sludge treatment works and observations on their removal from the effluent

Male breast cancer is a rare tumour in all parts of the world. About 1% of all breast cancers occur in men, but the male/female ratio is higher among black than among white populations. This effect can be seen in US cancer registries and even more markedly in African data. A positive correlation exists on a population scale between male breast cancer and prostate cancer. Seven case-control studies of male breast cancer are available, and a pooled analysis was conducted of the most commonly suspected risk factors. Male breast cancer appears to be associated with marital status: Mantel-Haenszel exposure odds ratio (EOR) for never married = 1.6; 95% confidence limits (CL) = 1.1, 2.3, religion (EOR for being Jewish = 2.1; 95% CL = 1.4, 3.2), previous breast pathology (EOR for positive history of benign breast disease = 2.7; 95% CL = 1.7, 4.2), gynaecomastia (EOR for positive history = 6.2, 95% CL = 3.4, 11.4), previous testicular pathology (EOR for positive history = 2.2; 95% CL = 1.5, 3.3), previous liver diseases (EOR for positive history = 1.6; 95% CL = 1.0, 2.4) and family history of breast cancer (EOR for first-degree relative with breast cancer = 2.5; 95% CL = 1.7, 3.7). No association is found with smoking history. Other potential risk factors such as reproductive history, education, occupation, anthropometric variables, association with various diseases, and specific exposures such as drug use, were not systematically evaluated in all studies and provide sometimes contradictory results, possibly due to small numbers of exposed subjects. Overall, the analytical epidemiology of male breast cancer presents similarities with the epidemiology of female breast cancer, with a potential role of factors related to hormonal status, relative hyperoestrogeny in men being potentially linked to increased risk of disease. Genetics may also play a role, with high risk linked to a familial history of breast cancer, and with a major risk in patients with Klinefelter's syndrome.

Review article: Epidemiology of male breast cancer. A meta‐analysis of published case‐control studies and discussion of selected aetiological factors

The three dominant oxidative biotransformations of estradiol were examined in 10 normal women and 33 females with breast cancer by using a recently devised radiometric method. Estradiol tracers, labeled with 3H specifically in the 17 alpha, C-2, or 16 alpha position, were used to measure both the rate and extent of 17 beta-ol oxidation (the initial metabolic step) and the subsequent 2- and 16 alpha-oxidative reactions. The mean +/- SEM values for the extent of extradiol metabolism at these three specific sites for the extent of estradiol metabolism at these three specific sites were 76.9 +/- 5.3%, 31.1 +/- 4.0%, and 9.3 +/- 0.8%, respectively in normal subjects. Corresponding data in patients with breast cancer--i.e., 73.0 +/- 4.2%, 32.7 +/- 2.7%, and 14.9 +/- 1.5%--revealed a significantly greater extent of 16 alpha-hydroxylation in the latter population. Because the 16 alpha-hydroxylated compounds (including estriol) are themselves potent estrogens, these changes may have important hyperestrogenic consequences that could have a bearing on the etiology of the disease.

https://www.pnas.org/content/pnas/79/9/3047.full.pdf

Abnormal oxidative metabolism of estradiol in women with breast cancer.

IN 1942 Farrow and Adair1 reported rapid progression of osseous metastases as a result of treatment with testosterone propionate in a male patient with cancer of the breast. In a second male patient, also with osseous metastases from an inoperable breast cancer, these authors performed a bilateral orchiectomy and obtained definite regression of the cancer, including marked decrease in the size of the ulcerative lesion of the breast, calcification of osteolytic bone metastases and complete relief of bone pain. The authors measured the urinary excretion of "estrogenic substance" and 17-ketosteroid before and after treatment and found a marked decrease in . . .

Urinary estrogen excretion in men with breast cancer.

The metabolism of 7,12-dimethylbenz(a)anthracene to hydroxymethyl derivatives differs in hepatic and mammary tissue homogenates. Countercurrent distribution and carrier recrystallization have been shown to be effective additional tools in the identification of 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 7,12-dihydroxymethylbenz(a)anthracene. In the hepatic tissue, 7,12-dimethylbenz(a)anthracene is transformed into all three of these metabolites whereas the mammary gland formed only the monohydroxy compounds. Pretreatment of rats with 3-methylcholanthrene induces a marked increase in 7,12-dimethylbenz(a)anthracene-metabolizing enzymes in the liver causing further conversion of the 7-hydroxymethyl-12-methylbenz(a)anthracene, 12-hydroxymethyl-7-methylbenz(a)anthracene, and 7,12-dihydroxy-7,12-dimethylbenz(a)anthracene to more polar components. In contrast, mammary gland caused a diminution but still detectable level of the carcinogenic 7-hydroxymethyl-12-methylbenz(a)anthracene and a noticeable increase in the conversion to 12-hydroxymethyl-7-methylbenz(a)anthracene. The data illustrate, for the first time, the ability of the mammary tissue to metabolize 7,12-dimethylbenz(a)anthracene.

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Comparative Metabolism of 7,12-Dimethylbenz(a)anthracene in Liver and Mammary Tissue

The daily excretion of estrone, estradiol, and estriol was determined for 22 normal women and 35 women with primary breast cancer. The excretion of the hormones (measured in microgram/24 hr) in the breast cancer group was elevated and showed a statistical significance of P less than 0.001. The same wide difference between the 2 groups was also noted when excretion was expressed in terms of the body area of the individuals and when women of similar ages were compared.

Charles E. Morreal

Papers

Urinary estrogen excretion in men with breast cancer.

Comparative Metabolism of 7,12-Dimethylbenz(a)anthracene in Liver and Mammary Tissue

Urinary Excretion of Estrone, Estradiol, and Estriol in Postmenopausal Women With Primary Breast Cancer

An improved method for the detection of estrone, estradiol, and estriol in low titer urine.

Isolation and identification of estriol in urine of castrated and adrenalectomized women receiving 4-14C-testosterone