Estrogens interact with mammary cells via specific estrogen receptors.
Epithelial growth factor receptor (EGFR) family is expressed in normal and malignant breast epithelial cells, and over expression in breast cancer for predicts for a poor outcome.
There is a discordance of receptor status between primary and metastatic lesions in approximately 25% of patients, therefore biopsy of metastatic lesions is recommended, if feasible for establishing estrogen receptor status.
EGFR promotes tumor progression, invasion, angiogenesis, and metastases, along with resistance to treatment by blocking apoptosis in breast cancer ( Nakamura Y et al).
Cross talk between EGFR and hormone receptors contributes to tumor behavior and response to hormonal therapy.
Estrogen receptor exists in two forms: ER-α and ER-β.
ER-α Is required for normal breast development and dramatic increases are noted in premalignant lesions.
ER-α andd ESR1 gene are implicated in most cases of breast cancer.
ESR1 mutations are significant in cases of metastatic and relapsed cases of breast cancer, and indicative of, or possibly driving treatment resistant disease conditions.
Alpha estrogen receptors induce pancreatic beta cell proliferation, increased beta cell insulin production and protect the beta cell from atresia.
Insulin and IGF 1 and 2 potentiate the effective alpha estrogen receptors on breast proliferation and uterine proliferation.
Alpha estrogen receptors effect on the brain increasing emotional sensitivity and thresholds.
Alpha estrogen receptors increase thyroid binding globulin making T3 and T4 less bioavailable.
Beta estrogen receptors block breast cell proliferation, increases multitasking, memory and verbal expression, important in recall and short-term memory, protects myocardium and endothelium, protect against colon cancer, and bronchodilator effect.
Estrogen beta receptor builds collagen and elastin in skin and vagina, increases lubrication and thickness of vaginal mucosa, increases ability for orgasm, and increases parasympathetic effect on clitoral enlargement during sexual activity.
Estrogen receptor beta decreases urinary urgency and frequency, decreases pelvic floor tone, and with progesterone stabilizes LH activity in menopause, increases sex hormone binding globulin, improves cholesterol, and improves elasticity of arteries, increases cardiac perfusion, and diminishes diastolic dysfunction.
ER functions as a nuclear transcription factor and estrogen action in the nucleus is termed nuclear initiated spheroid signaling (NISS).
Estrogen receptors play a key role in normal breast development and in progression of breast cancer.
Estrogen receptor expression in primary breast cancer confers a favorable prognosis independent of stage of cancer.
The estrogen receptor is a week prognostic marker, but is a strong predictor of response to antiestrogen therapy.
Approximately 75% of patients with postmenopausal breast cancer are ER positive. ER positive tumors are associated with better survival than those with ER low or no ER expression. 5-year survival is approximately 10 to 15% better for women with ER positive breast cancer than those ER negative.
Approximately 70-80% of breast cancers express ERα.
Approximately 70% of BC tumors express estrogen and/or progesterone receptors.
In estrogen receptor-positive breast cancer, androgen receptor expression occurs in 67%-88% of cases and is associated with an improved outcome.
Hormone receptors are the primary transcription factors driving oncogenesis in hormone receptor + BC.
Both ER and PR are targets of anti-estrogen therapy, and are predictors of response to such therapy.
Estrogen stimulation of ER causes recruitment to specific sites across the genome via specific epigenetic events restricting recruitment to a subset of potential sites.
Positive tumors are characterized by molecular markers of normal luminal epithelial cells which can be subdivided into subgroups, with the luminal subgroup with the highest expression levels of luminal/ER associated genes having the poorest 5-year survival after adjuvant therapy compared the those with low to moderate expression of these genes.
Women with early stage breast cancer with ER negative lesions have a peak annual hazard of recurrence of 18.5% at 1-2 years after surgery that decline thereafter to rate of 1.4% in years 8-12.
Annual hazard rate of recurrence for women with early stage breast cancer that is ER positive peaks at 11.0% in years 2-3, and a risk of approximately 5% through year 12.
ER+ lesions associated with slow growth, better differentiation, and a slightly better prognosis.
The positive predictive value of ER expression is 50% or less, meaning only half, or less, of patients who receive endocrine therapy for ER+ cancers benefit.
Tumors that express both ER and PR respond well to tamoxifen with an objective response rate of 80%, while patients with ER+ but PR- lesions have only a 30% chance of responding.
TNBC late recurrences are relatively rare, unlike ER positive cancers, in which up to 50% of distant recurrences develop after 5 years.
Levels are low in normal breast tissue and high levels correlate with increased risk of breast cancer.
Levels increase with age in some ethnic groups of women and are higher in white than in black or Japanese women.
Primary target for hormonal treatment of breast cancer and ER expression is a reliable marker predicting response to such therapy.
ER expression makes the strongest impact on the gene expression patterns of breast cancers.
The ER- group of tumors can be divided into three subgroups: adipose enriched normal breast tissue markers for normal breast, basal epithelial cells and expression of the oncogene ERBB2.