Dissociation between steroid receptor expression and cell proliferation in the human breast (original) (raw)
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Estrogen responsiveness and control of normal human breast proliferation
Journal of mammary gland biology and neoplasia, 1998
Our understanding of the hormonal control of the proliferation of normal human breast epithelium is still surprisingly meager. However, the results of a number of recent studies have confirmed that estrogen is the major steroid mitogen for the luminal epithelial cell population (the usual targets for neoplastic transformation). Estrogen seemingly exerts its effects on cell division indirectly as there is complete dissociation between the population of luminal epithelial cells expressing the estrogen receptor (ER)4 and those that proliferate. We suggest that the ER-negative proliferating cells represent a precursor or stem cell population that differentiates to ER-containing, nonproliferative cells. In turn, these ER-positive cells act as 'estrogen sensors' and transmit positive or negative paracrine growth signals to the precursor cells depending on the prevailing hormonal environment. As yet there is no direct evidence supporting this hypothesis but we suggest ways in which...
Breast Cancer Research and Treatment, 1997
High serum concentrations of estradiol (E 2 ) equivalent to those observed in the luteal phase of the menstrual cycle stimulate both epithelial cell proliferation and progesterone receptor (PgR) expression in normal human breast tissue xenografted into athymic nude mice. We report here the results of further investigations designed to determine whether the induction of PgR expression and proliferation require different E 2 concentrations and whether proliferating cells expressed the PgR. In untreated normal breast xenografts, the PgR was virtually undetectable and proliferation was at basal levels. Progesterone (Pg) treatment alone had no effect compared to no treatment. Treatment with E 2 at follicular phase serum concentrations maximally increased PgR expression but was without effect on proliferation. However, treatment with E 2 at luteal phase serum concentrations, alone or in combination with Pg, significantly increased both the PgR content and the proliferation of the breast epithelium. These experimentally derived data reflected the observations made on normal breast tissue at surgical biopsy where PgR content was similar in both halves of the menstrual cycle, whereas proliferation was significantly higher in the luteal phase. Finally, using double labelling techniques, it was demonstrated that proliferating epithelial cells rarely expressed PgR in normal breast tissue obtained at surgical biopsy. These results suggest that the threshold of E 2 required to induce PgR expression in normal human breast epithelial cells is lower than that required to induce proliferation and that the majority of proliferating breast cells do not express the PgR.
Regulation of Estrogen Concentrations in Human Breast Tissues
Annals of the New York Academy of Sciences, 1990
For many years estrogens have been known to be an important factor in the growth biology of human breast tumors. The extent to which they are directly involved in the pathogenesis of the disease is unclear; most investigators consider that their role is not primary, but good biological, clinical, and biochemical evidence indicates that estradiol particularly is a major growth factor in tumors that contain estrogen receptors.' These observations have stimulated a great deal of research into the metabolism of steroid hormones in women with breast cancer and also in animal models, although it is recognized that animal models pose major problems in interpreting results in a human clinical context.
Breast Cancer Research and Treatment, 1990
The purpose of this study was to determine the distribution of ER+ (estrogen receptor) and PR+ (progesterone receptor) epithelial cells in normal mammary tissue or in tissue in contact with or involved in benign or malignant processes. Three important findings emerged from this study. First, a true dissociation was observed between ER+ and PR+ cells in mammary tissue. In premenopausal women some cells express only progesterone receptors. In premenopausal normal tissue, regardless of the menstrual cycle status, 6% of cells are ER+ and 29% PR+. Second, during the menstrual cycle the percentage of positive cells varies. This finding would indicate a change in cell recruitment rather than in intracellular levels. Finally, specific changes in the proportion of positive cells in normal tissue in contact with epithelial proliferations were noted. This finding suggests the possibility of either a diffusible factor or a cellular pathological process spreading beyond areas displaying morphological changes.
Effects of estradiol and progestogens on human breast cells: regulation of sex steroid receptors
Taiwanese journal of obstetrics & gynecology, 2013
To examine the effects of 17β-estradiol (E2) and progestogens, used in hormone therapy, on estrogen receptors (ER), progesterone receptors (PR), and human breast tumor cell growth. MCF-7 cells were incubated in pure E2 (1 nM and 10 nM) as well as in E2 in conjunction with 10 nM progestogens, including progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone acetate (NET), and cyproterone acetate (CPA). Cell proliferation, apoptosis, expression of caspase-3, and both ER and PR isoforms were evaluated. Caspase-3 was significantly diminished in cultures with only E2, whereas ERα significantly increased. A significant increase of caspase-3 in addition to the entire abolishment of E2-induced augmentation of ERα was observed in 1 nM E2 plus MPA and 10 nM E2 plus NET, whereas PR isoform B (PRB) was significantly increased. The ratios of apoptosis: proliferation significantly increased in 1 nM E2 plus progestogens (except P4) and 10 nM E2 plus NET. The changes of the PRA/PRB rat...
Estrogen receptor ? expression in normal human breast epithelium is consistent over time
International Journal of Cancer, 2002
If increased expression of estrogen receptor ␣ (ER) in benign breast epithelium increases susceptibility to breast cancer, such overexpression should be stable over time. There are no published data regarding this important aspect of ER expression in breast epithelium. We examined the temporal consistency of ER expression in the normal breast tissue of 28 women who had 2 separate breast surgical procedures, at least 6 months apart (mean interval, 2.8 years). Paraffin embedded breast tissue blocks containing an adequate sample of normal breast epithelium and no cancer, were sectioned and processed using the 6F11 antibody and standard immunohistochemical techniques. The ER labelling index (ER LI) was calculated by counting a mean of 2,000 epithelial cells. The median ER LI at first sampling was 13.6 and at second sample 15.5, with R 2 ؍ 0.34 and p ؍ 0.001. The ER LI was categorized into high and low values, using a threshold of 10. Twenty-four women (85.7%) showed concordance of high and low expression between the 2 samples (p ؍ 0.002). There were 11 women who were premenopausal at both time points. Among them, much of the variation in ER LI was explained by differences in the menstrual cycle day at the time of sampling and adding the day of cycle to the regression model substantially improved the correlation between first and second labeling indices. These data suggest that ER expression of normal breast tissue is fairly consistent over time and support the notion that overexpression of ER in normal epithelium is a constant feature of the high risk breast.
Steroid receptors in human breast cancer
Trends in Endocrinology & Metabolism, 2004
Ovarian steroids, acting through nuclear receptors, are crucial players in normal breast development and cancer. Estrogen, in particular, is the focus of breast cancer therapies because tumours are often dependent on this steroid for growth. Recently, novel genes and/or protein isoforms of receptors for both estrogen and progesterone have been discovered, leading us to reappraise their roles in breast development and cancer. Recognition of changes in estrogen receptor biology that occur in the transition from normal development to cancer has emphasized its contribution to tumorigenesis. In addition, complex interactions with other signalling pathways, particularly growth factor pathways, have recently come to the forefront. These interactions might explain resistance to endocrine treatments and offer solutions in terms of novel therapeutic targets.
Estrogen and progesterone receptors in the normal female breast
Cancer research, 1991
We have studied estrogen receptor (ER) and progesterone receptor (PR) in normal breast by immunocytochemistry using tissue biopsies and fine needle aspirates (FNA) and, in the case of ER, by enzyme immunoassay. For ER we found a high degree of reproducibility for biopsies taken from the upper outer quadrant: FNA, r = 0.56 (P less than 0.002); tissue section immunocytochemistry, r = 0.89 (P less than 0.0001); and enzyme immunoassay, r = 0.76 (P less than 0.0001). For PR, FNA (r = 0.56, P less than 0.002) and tissue section (r = 0.97, P less than 0.0001) were also found to be reproducible techniques. Using enzyme immunoassay, we were able to measure ER accurately in normal breast tissue. In 59 samples we found a range of 0-37 fmol/mg cytosol protein (mean, 4 fmol/mg). In an age-matched group of 126 women with breast cancer, we found a significantly higher ER [range, 0-139 fmol/mg; mean, 37 fmol/mg (P less than 0.001)]. We then analyzed the ER and PR content of FNAs obtained from the u...
Cancer research, 1993
Estrogen is essential for the growth of the normal mammary gland and most estrogen receptor (ER)-positive mammary carcinomas. To better understand the differences between the estrogen response pathways in normal and tumor cells, we have stably transfected ER-negative immortal, nontumorigenic human mammary epithelial cells and ER-negative breast cancer cells with an ER-encoding expression vector. Unexpectedly, estrogen treatment (1.0 nM) inhibited the proliferation of ER-transfected nontumorigenic and tumor-derived cells. The control transfectants and parental cells exhibited no response to estrogen concentrations as high as 1.0 microM. This inhibitory effect was attributed to a decreased growth rate and a perturbation of the cell cycle distribution by estrogen treatment of the ER transfectants. The inhibitory response was blocked by cotreatment with the antiestrogen ICI 164,384 as predicted for a pure antagonist of estrogen action. However, treatment with the antiestrogen hydroxytam...