Abnormal estrogen metabolism and tissue estrogen receptor proteins in breast cancer

Abstract

Estradiol 17β and weaker uterotropic metabolites oxidized on C2, C6, and C16 (“impeded” estrogens) mutually compete for cytoplasmic proteins of uterus, vagina, and breast, which appear implicated in the initial concentration of C18 steroids, activating target tissues. Experimental and human endemiologic evidence suggests that the relative concentrations of estradiol 17β and of estriol, the principal human “impeded” estrogen, sustained chronically in the vicinity of breast tissues may influence the risk of mammary carcinogenesis. Impeded estrogens have not yet been proven to be carcinogenic in any species. Estriol has failed to induce breast tumors in 30 Sprague‐Dawley female rats over 250 days of observation in our experience. Estriol, along with progesterone, is one of the 2 major hormones produced and excreted in pregnancy. It inhibits several of the tissue tropic actions of estradiol 17β, presumably by displacing the latter from receptor proteins of the cytoplasm and nucleus, which has been demonstrated for uterine, vaginal, and mammary tissues. Several investigations by different analytic methods indicate a relative deficiency of estriol production and excretion from adrenocortical and gonadal sources in about one quarter of healthy, nonpregnant Caucasian premenopausal women; two thirds of patients with fibrocystic disease of the breast and with untreated breast cancer may excrete subnormal estriol concentrations. In induced rat mammary cancers, estriol can inhibit estradiol binding to homogenates. The hypothesis is advanced that estriol plays a significant anticarcinogenic role in the human female, accounting in part for the reduced expectancy of mammary cancer in Japanese women, in whom low estriol excretion has not yet been reported, and in women with multiple pregnancies in their early child‐bearing years, or after early castration. Estriol should be an effective form of endocrine therapy for hormone‐dependent breast cancer, since it retains much of its capacity to bind to estrogen receptor proteins in tissues, substituting for estradiol 17β.

The association of body weight with recurrent cancer of the breast

“…A high proportion of estriol, a relatively weak estrogen, is purported to moderate the carcinogenic influences of the other two. 5 Wynder and associates postulated an altogether different mechanism by which a high fat diet might promote tumor growth.14 In rats a high fat diet increases prolactin production and promotes growth of DMBA mammary cancers.…”

Advancement of mass spectrometry-based proteomics technologies to explore triple negative breast cancer

“…In recent decades genomic and transcriptomic technologies have led to the identification and characterization of several breast cancer-related genes. These include BRCA1 5 , ErBB2 6 (also known as HER2), ESR1 7 (also known as ER) and protein kinases, such as ATM, 8 that acquire driver mutations in certain human breast cancers 9 . The advent of cDNA microarray technology and subsequently RNAseq has enabled us to look at global patterns of gene expression in breast cancer cells, which can be classified according to distinct molecular characteristics 10 .…”

Genetic predisposition to carcinoma of the breast: Multiple human genotypes for estrogen 16 alpha hydroxylase activity in caucasians

“…These observations support previous reports from this and other laboratories, that some type of relationship exists between mammary carcinoma in Caucasian pre-and postmenopausal women, and the biosynthesis and excretion of estriol relative to the primary estrogens secreted by the ovary. Since estriol binds with less affinity to the rat breast or uterine receptor proteins than estradiol 17B (41,42), any competitive inhibitory effects which it might have upon estrogen induction of breast carcinogenesis must be the result of a chronic endogenous balance sustained between estriol and circulating ovarian steroids. Estriol concentration in body fluids depends chiefly upon the rate of 16 alpha hydroxylase activity in tissues such as liver and small intestine, since it is rapidly excreted by the kidney (10).…”