Estrogen and Progesterone Receptors in Benign Breast Epithelium

Abstract

H Abstract: Estrogen and progesterone are necessary for lobulo-alveolar development of the human breast, and there is an abundance of epidemiologic literature implicating estrogen and possibly progesterone exposure as promoters of breast malignancy. The investigation of estrogen receptor (ER) and progesterone receptor (PgR) distribution in normal and benign breast tissue may be a measure of susceptibility of the tissue to these hormones. Earlier data from radioligand binding assays showed that benign breast tissue expressed little or no ER; newer immunohistochemical (IHC) methods have led to the investigation of benign breast tissue from at least 1243 women in 12 studies in the last 9 years. These show that the level of expression of ER and PgR in normal breast epithelium is significantly lower than in receptor positive carcinomas. lmmunostaining patterns for both receptors show a great deal of heterogeneity. There is general agreement that stromal and myoepithelial cells are negative for both ER and PgR. A growing body of evidence suggests that PgR is the dominant sex steroid receptor in the normal breast. Mean values for PgR positive cells in breast epithelium range from 24% to 29%; ER is positive by IHC in 3% to 15.6% of normal breast epithelial cells. No firm conclusions are possible as yet regarding overexpression in proliferative epithelium. There is agreement that the proportion of ER positive cells declines in the second half of the menstrual cycle, but there is no clear cut relationship between PgR positivity with the menstrual cycle. Oral contraceptive use appears to decrease the proportion of ER positive cells, and increase mammary epithelial proliferation. A recent case-control analysis of epithelial ER and f k~R status reports an association of ER positive benign epithelium with the presence of cancer in the Address correspondence and reprint requests to Seema A. Khan, M.D., 750 East A d a m Street, Syracuse, NY 13210, U.S.A. 0 1995 Blackwell Scrence lnc., 1075-122X/95/%10.50/0 The Breast]oumal, Volume 1, Number 4, 1995 251-261 breast. Future research should include a systematic quantitative analysis of receptor expression in epithelial proliferative lesions, and the longitudinal follow-up of women who have had receptor testing on benign breast tissue.strogen exposure is a well established risk factor for E breast cancer. Estrogen is a mitogen for breast cancer cells in culture, and also for normal breast epithelial cells in-vivo, although progesterone is an important mitogen for the normal breast (1,2). Estrogen effect on target tissues is mediated by its receptor, which is markedly overexpressed (relative to benign tissue) in about two thirds of invasive breast cancers. The study of estrogen receptor expression in normal and benign breast epithelium is therefore of interest given the links between estrogen, its receptor, breast epithelial proliferation, and the subsequent non-obligate progression to malignancy. This line of reasoning fits well with the model that non-genotoxic carcinogens can act ...

Breast Cancer Genetics

“…On the other hand, LCIS and hyperplasia with or without atypia do not require a treatment intervention and are often diffusely distributed, which suggests that they can be utilized as response biomarkers in intermediate and long-term chemoprevention trials. 223,225,226,[229][230][231] Other tissue-based biomarker abnormalities, which are potentially reversible and are currently being explored in phase II trials, have already been presented in this chapter and include elevated proliferation indices such as Ki-67 and PCNA [181][182][183][184] ; ER overexpression 232,233 ; markers of oncogene overexpression such as Her2/neu and EGFr [190][191][192] ; altered levels of insulin-like growth factor receptor (IGFR), IGF-1, and IGF binding protein-3 (IGFBP-3) [234][235][236][237][238][239] ; indicators of apoptotic imbalance including an increased bcl-2/bax ratio [185][186][187] ; markers of disordered cell signaling such as p53 protein accumulation or nuclear exclusion [193][194][195][196][197] ; altered levels of p16, p21, p27, cyclin D 1 , and cyclin E [240][241][242][243][244][245][246][247][248] ; alteration of differentiation signals such as c-myc and related proteins [249]…”

Differentiation and Cancer in the Mammary Gland: Shedding Light on an Old Dichotomy

“…Here, estrogen acts analogous to a tumor promotor, because ER-positive tumor cells will not develop into tumors unless estrogen is provided either from the mouse or exogenously through the diet (Soule and McGrath, 1980). This, and the fact that estradiol increases the incidence of mammary tumors in mice and rats (Snedeker and Diagustine, 1996), raise an interesting question, namely whether estrogen acts as a carcinogen for normal cells (Khan, 1995). This question has been difficult to answer in a physiological setting because normal breast epithelial cells-as mentioned above-should definitely not be considered a homogeneous population in terms of ER expression.…”

“…It has been quite a task to extract sensible information about ER function under normal and malignant conditions based on the standard tissue culture assays . The fact is, that if measured biochemically, the estrogen receptor is expressed in about 60% of breast carcinomas but is hardly measurable in normal breast tissue (Ricketts et al, 1991;Khan, 1995). By this definition then, the ER-negative carcinomas should be the most highly differentiated tumors in that, in this respect, they would resemble normal tissue the most!…”

“…Furthermore, if one accepts that normal breast tissue is essentially devoid of ERs, then ER-positive carcinomas would have to arise from a multipotent stem cell similar to those of teratocarcinomas (Sell and Pierce, 1994). However, once immunocytochemical assays became available, it was discovered that the sensitivity of the original biochemical ER analysis was too low to measure the level of ER expression in normal breast tissue Khan, 1995). Using the assay, the level of expression in normal breast tissue from reduction mammoplasties was found to be an average of 7% of the luminal epithelial cells, and the stroma was devoid of receptor expression Khan, 1995).…”

“…However, once immunocytochemical assays became available, it was discovered that the sensitivity of the original biochemical ER analysis was too low to measure the level of ER expression in normal breast tissue Khan, 1995). Using the assay, the level of expression in normal breast tissue from reduction mammoplasties was found to be an average of 7% of the luminal epithelial cells, and the stroma was devoid of receptor expression Khan, 1995). Based on studies in the mouse, it had been hypothesized previously that the ERs in the stroma signal to the epithelium.…”