Use of the Autopsy to Study Ontogeny and Expression of the Estrogen Receptor Gene in Human Breast

Historically, autopsies have been a valuable resource for morphologic studies of the human breast, and have been used in conjunction with radiologic evaluation and epidemiology to provide information about population prevalence of pre-malignant and malignant disease. More recently, well-preserved post-mortem breast tissue has also been used to evaluate the status of genes and their expression. Using molecular techniques and immunohistochemistry, quantitation of gene expression and localization of proteins of hormone receptors, growth factor receptors, growth factors, cell-proliferation related antigens and proto-oncogenes can be evaluated in autopsy-derived breast tissue. Expression of the estrogen receptor (ER)³ gene at the mRNA and protein product levels has been evaluate d in breast tissue from infants, children, adolescent girls, and adult women in various phases of the menstrual cycle, pregnancy and post-menopausal. The results of these studies support a role for the ER gene in early as well as pubescent breast development, and also in normal cyclical and abnormal cell proliferation in the terminal-duct-lobular-units (TDLU) of adult women.     

Estrogen Responsiveness and Control of Normal Human Breast Proliferation

Our understanding of the hormonal control of theproliferation of normal human breast epithelium is stillsurprisingly meager. However, the results of a number ofrecent studies have confirmed that estrogen is the major steroid mitogen for the luminalepithelial cell population (the usual targets forneoplastic transformation). Estrogen seemingly exertsits effects on cell division indirectly as there iscomplete dissociation between the population of luminalepithelial cells expressing the estrogen receptor (ER)4and those that proliferate. We suggest that theER-negative proliferating cells represent a precursor or stem cell population that differentiates toER-containing, nonproliferative cells. In turn, theseER-positive cells act as 'estrogen sensors' and transmitpositive or negative paracrine growth signals to the precursor cells depending on theprevailing hormonal environment.As yetthere is nodirectevidence supporting this hypothesis but we suggestways in which it may be obtained. The implication ofthese studies is that inhibition of luminalepithelial proliferation with tamoxifen or pureantiestrogens or by preventing ovarian steroid secretionshould be an effective strategy for the prevention ofbreast cancer. In addition, we may be able to predictthe risk of breast cancer in an individual by measuringthe intrinsic estrogen sensitivity of her breastepithelium. Finally, study of the paracrine mechanisms of growth control in the normal human breastmay provide new, more specific, therapeutic targets forbreast cancer prevention.     

The Estrogen Receptor: A Logical Target for the Prevention of Breast Cancer with Antiestrogens

A strategy for the prevention of breast cancerhas been refined over the last century beginning withthe first observation that oophorectomy caused diseaseregression in some patients, to the identification of the estrogen receptor some 60 years later,and finally to the synthesis of the first nonsteroidalantiestrogen. Tamoxifen was the first clinically usefulantiestrogen and has been used for the treatment of breast cancer for the last twenty-one yearsin the United States. It is therefore a logicalprogression that antiestrogens are now recognized asuseful agents for the prevention of breast cancer. We will discuss the estrogen receptor as a targetfor the treatment and now the prevention of breastcancer. Data from the National Surgical and BowelProject (NSABP)⁴ tamoxifen prevention trial will be discussed with the preliminary resultsof two other European studies. The status of breastcancer prevention to date involves the comparison of thecurrent standard of prevention, tamoxifen, with the osteoporosis prevention drug, raloxifene inan ongoing trial called Study of Tamoxifen andRaloxifene (STAR).     

Mammary Gland Growth and Development from the Postnatal Period to Postmenopause: Ovarian Steroid Receptor Ontogeny and Regulation in the Mouse

Ovarian steroid hormones play a critical role inregulating mammary gland growth and development. Themammary gland sequentially acquires and cyclicallyexhibits proliferative responses to estrogen and/or progesterone from birth to postmenopause. Thefocus of this review is to presentour currentunderstanding of estrogen and progesterone receptordistribution in epithelial and stromal cells and theirfunctions in relation to mammary gland development.Insights gained from the study of the normal mammarygland are relevant to our understanding of theconditions which may predispose women to the developmentof breast cancer as well as to alterations inhormonal regulation that occur in breastcancer.     

Role of the Androgen Receptor in Human Breast Cancer

Although the androgen receptor (AR)³is often co-expressed with the estrogen receptor (ER)and progesterone receptor (PR) in human breast tumors,its role in breast cancer is poorly understood. Specific growth stimulatory and inhibitory actions ofandrogens have been described in human breast cancercell lines. The mechanisms by which androgens exertthese contrasting growth effects are unknown. A commonly utilized second line therapy for the treatmentof advanced breast cancer is high dosemedroxyprogesterone acetate (MPA). Although MPA, asynthetic progestin, was thought to act exclusivelythrough the PR, the androgenic side-effects observed in womentaking MPA suggest that its action may also be mediatedin part by the AR. In support of this hypothesis, thelevel of AR measured by radioligand binding in primary breast tumors was correlated with theduration of response to MPA treatment following failureof tamoxifen therapy. Recent data suggest that thepresence of structurally altered AR in breast cancers may account for unresponsiveness to MPA in someof these cases. Further studies are warranted todetermine the role of AR mediated pathways in regulatingbreast tumor growth. In particular, identification of androgen-regulated genes may lead to newpossibilities for the hormonal treatment of breastcancer.     

新辅助化疗对乳腺癌雌孕激素受体表达的影响

目的：探讨新辅助化疗对乳腺癌雌孕激素受体表达的影响。方法：应用免疫组化方法检测60例新辅助化疗治疗的乳腺癌和84例未术前化疗的乳腺癌标本化疗前或术前和术后ER、PR的表达情况,比较两组ER、PR表达变化的差异。结果：新辅助化疗组ER、PR的阳性率分别从化疗前的51.67%、43.33%变为术后的71.67%、56.67%,而对照组基本没变化;新辅助化疗组ER、PR表达状态发生改变分别为26.67%、16.67%,表达强度改变为38.33%、43.33%,对照组ER、PR表达状态发生改变分别为3.57%、1.19%,表达强度改变为11.9%、11.9%,差异具有显著性（P〈0.01）。结论：新辅助化疗影响乳腺癌雌孕激素受体的表达并有可能上调激素受体表达。     

Estrogen and Progesterone Receptor and p53 Gene Expression in Adenoid Cystic Cancer

Objectives The current study examined the role of estrogen receptors (ER), progesterone receptors (PR) and p53 expression in adenoid cystic carcinoma (ACC) to determine if simple expression or possible overexpression of these products might influence the development and natural course of this cancer. Study Design ER and PR status and p53 overexpression were retrospectively evaluated utilizing immunohistochemical evaluation of 47 ACC specimens. Methods Formalin-fixed paraffin-embedded tissues from 47 ACC specimens and 47 samples of normal salivary gland tissue were evaluated histochemically for the presence of ER, PR and p53. Immunoreactivity was scored using a 0 to +3 scale in which staining was either (0) negative, (+1) spotty, (+2) weakly positive, or (+3) strongly positive. Results ER was expressed in 8 of 47 tumors while PR was expressed in 4 of 47 tumors. p53 aberrations were demonstrated in 26 of 47 tumors. Tumors showed varying degrees of immunopositivity ranging from 0 to +3. Conclusions These studies suggest that p53 aberrations may be involved in ACC tumor progression and that ER and PR may play a role in ACC development.     

Loss of the Vitamin D Receptor in Human Breast Cancer Cells Promotes Epithelial to Mesenchymal Cell Transition and Skeletal Colonization

Expression of the vitamin D receptor (VDR) is thought to be associated with neoplastic progression. However, the role of the VDR in breast cancer metastasis to bone and the molecular mechanisms underlying this process are unknown. Employing a rodent model (female Balb/c nu/nu mice) of systemic metastasis, we here demonstrate that knockdown of the VDR strongly increases the metastatic potential of MDA-MB-231 human breast cancer cells to bone, resulting in significantly greater skeletal tumor burden. Ablation of VDR expression promotes cancer cell mobility (migration) and invasiveness, thereby facilitating skeletal colonization. Mechanistically, these changes in tumor cell behavior are attributable to shifts in the expression of proteins involved in cell adhesion, proliferation, and cytoskeletal organization, patterns characteristic for epithelial-to-mesenchymal cell transition (EMT). In keeping with these experimental findings, analyses of human breast cancer specimens corroborated the association between VDR expression, EMT-typical changes in protein expression patterns, and clinical prognosis. Loss of the VDR in human breast cancer cells marks a critical point in oncogenesis by inducing EMT, promoting the dissemination of cancer cells, and facilitating the formation of tumor colonies in bone. © 2019 American Society for Bone and Mineral Research.     

Estrogen and Progesterone Receptors in Primary Breast Cancer

Abstract: The purpose of this study was to determine biological variable profiles and survival experiences associated with different combinations of estrogen receptor (ER) and progesterone receptor (PR) status (ER+PR+, ER+PR-, ER-PR+, ER-PR-). Data were collected and provided by the State Health Registry (SHR) of Iowa, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Significant associations were determined for individual prognostic variables with each ER/PR categories, and overall survival was compared between each ER/PR category. Multiple logistic regression analyses were conducted to determine all significant prognostic variables associated with each ER/ PR category. All women diagnosed with primary breast cancer in Iowa from 1990 through 1992 were included in this study (N = 6, 178). In unadjusted analyses, Caucasian woman and older women were significantly more likely to be ER + PR+, while African American women and younger women were significantly more likely to be ER-PR-. In multivariate analyses, each ER/PR category was associated with distinct profile of age, menopausal status, histologic grade, and histology. Survival was best for women in the ER+PR+ group, followed, in decreasing order, by ER+PR-, ER-PR+, and ER-PR-. In this population-based study of primary breast cancer, combined hormone receptor status was a significant prognostic determinant for primary breast cancer, and was associated with distinct biological variables and survival experiences. In combination with other variables such as age, menopausal status, tumor histologic grade, and tumor histology, combined hormone receptor status can provide important prognostic information to the clinician.?     

Estrogen Receptor Alpha in Human Breast Cancer: Occurrence and Significance

Estrogens have long been recognized as being important for stimulating the growth of a large proportion of breast cancers. Now it is recognized that estrogen action is mediated by two receptors, and the presence of estrogen receptor (ER)³ correlates with better prognosis and the likelihood of response to hormonal therapy. Over half of all breast cancers overexpress ER and around 70% of these respond to anti-estrogen (for example tamoxifen) therapy. In addition, the presence of elevated levels of ER in benign breast epithelium appears to indicate an increased risk of breast cancer, suggesting a role for ER in breast cancer initiation, as well as progression. However, a proportion of ER-positive tumors does not respond to endocrine therapy and the majority of those that do respond eventually become resistant. Most resistant tumors remain ER-positive and frequently respond to alternative endocrine treatment, indicative of a continued role for ER in breast cancer cell proliferation. The problem of resistance has resulted in the search for and the development of diverse hormonal therapies designed to inhibit ER action, while research on the mechanisms which underlie resistance has shed light on the cellular mechanisms, other than ligand binding, which control ER function.     

Sex‐Dependent,Osteoblast Stage‐Specific Effects of Progesterone Receptor on Bone Acquisition

The role of the progesterone receptor (PR) in the regulation of sexual dimorphism in bone has yet to be determined. Here we utilized genetic fate mapping and Western blotting to demonstrate age‐dependent PR expression in the mouse femoral metaphysis and diaphysis. To define sex‐dependent and osteoblast stage–specific effects of PR on bone acquisition, we selectively deleted PR at different stages of osteoblast differentiation. We found that when Prx1‐Cre mice were crossed with PR floxed mice to generate a mesenchymal stem cell (MSC) conditional KO model (Prx1; PRcKO), the mutant mice developed greater trabecular bone volume with higher mineral apposition rate and bone formation. This may be explained by increased number of MSCs and greater osteogenic potential, particularly in males. Age‐related trabecular bone loss was similar between the Prx1; PRcKO mice and their WT littermates in both sexes. Hormone deficiency during the period of rapid bone growth induced rapid trabecular bone loss in both the WT and the Prx1; PRcKO mice in both sexes. No differences in trabecular bone mass was observed when PR was deleted in mature osteoblasts using osteocalcin‐Cre (Bglap‐Cre). Also, there were no differences in cortical bone mass in all three PRcKO mice. In conclusion, PR inactivation in early osteoprogenitor cells but not in mature osteoblasts influenced trabecular bone accrual in a sex‐dependent manner. PR deletion in osteoblast lineage cells did not affect cortical bone mass. © 2017 American Society for Bone and Mineral Research.     

ER基因CpG岛甲基化的表达及其临床意义

目的:研究ER基因表达及CpG岛甲基化状况与胃癌生物学行为和预后的关系.方法:分别应用免疫组化SP法和限制性内切酶PCR法分析91例胃癌ER的表达和30例胃癌ER墓因CpG岛甲基化的状况.结果:胃癌ER阳性率为38%(35/91),其中高分化腺癌10%(3/30),分别与低分化腺癌43%(13/30)、未分化腺癌53%(8/15)、粘液癌63%(5/8)及印戒细胞癌75%(6/8)比较皆具有显著性差异(P＜0.05);伴淋巴结转移组为55%(11/20),未转移组22.5%(9/40),差异有显著性(P＜0.05).正常胃粘膜ER基因CpG岛未甲基化,而胃癌呈高度甲基化40%(12/30)(P＜0.05).结论:ER在胃癌中的表达与浸润、转移有关,ER阳性胃癌生物学行为差,ER基因CpG岛甲基化可能是胃癌中ER失表达的分子机制.     

Lack of Either Estrogen or Progesterone Receptor Expression Is Associated with Poor Survival Outcome among Luminal A Breast Cancer Subtype

Background

This study was designed to evaluate the impact of lack of either estrogen receptor (ER) or progesterone receptor (PR) on characteristics and outcomes among luminal A breast cancer subtype treated with endocrine with or without chemotherapeutic agents.

Methods

The luminal A subtype was categorized into three subgroups: ER+/PR+, ER+/PR?, and ER?/PR+. All tumors were human epidermal growth factor receptor 2 (HER2) negative. Clinicopathological features and survival were analyzed using the Severance Hospital dataset (n = 1,180) and were validated by the nationwide Korean Breast Cancer Society (KBCS) registry (n = 9,916).

Results

Despite the different distribution of ER/PR status, tumor stage, grade, and local therapies between the two datasets, similarly ER+/PR+ showed smaller size and good differentiation, ER+/PR? patients had the oldest age at diagnosis, and ER?/PR+ was associated with the youngest age at onset and grade III tumor. Single hormone receptor-positive subgroups demonstrated worse disease-related outcomes than the ER+/PR+ subgroup. These associations were confirmed by the KBCS dataset. This trend was also demonstrated in the subpopulation of 1,944 patients with Ki-67 < 14 %. Inferior survival of single receptor-positive tumors was more definite among node-positive patients even when receiving both chemo-endocrine therapies.

Conclusions

Current results suggest that the luminal A subtype is also heterogeneous and each subgroup has unique clinicopathologic characteristics. Lack of either ER or PR expression is associated with worse survival, especially among node-positive luminal A subtype.     

CXCR4在乳腺癌中的表达及意义

目的：研究CXCR4在人乳腺癌及癌前病变中的表达情况,并分析其与乳腺癌相关临床病理指标之间的关系。方法：采用免疫组织化学方法（IHC）研究CXCR4在23例乳腺导管上皮增生,26例重度不典型导管上皮增生,34例乳腺导管内癌（DCIS）和126例浸润性乳腺癌组织中的表达差异情况;分析浸润性乳腺癌中CXCR4表达与腋窝淋巴结受累数目、临床分期、肿瘤直径、组织学分级等临床病理指标的相关性。结果：CXCR4在乳腺导管上皮增生、重度不典型导管上皮增生、乳腺导管内癌、浸润性乳腺癌组织中的阳性表达率依次为8.70%、23.08%、56.25%、60.32%,表达水平呈现增高趋势,具有随病变恶性程度加重而逐步增高的趋势（P〈0.05）;但导管内癌和浸润性乳腺癌两组表达水平无明显差别。CXCR4在浸润性乳腺癌中的表达与腋窝淋巴结受累数目、临床分期呈正相关,与肿瘤直径、组织学分级无明显相关性。淋巴结阳性组浸润性乳腺癌CX-CR4阳性表达率高于淋巴结阴性组（P〈0.05）。结论：CXCR4可能是乳腺癌发生的早期分子事件;CXCR4在浸润性乳腺癌中的表达与乳腺癌进展的临床病理指标相关,可作为乳腺癌的诊断指标;CXCR4可能成为乳腺癌治疗的新靶点。     

雌激素受体β与乳腺癌

目的 探讨雌激素受体β（ERβ）在乳腺癌方面的研究进展，方法 采用文献回顾方法。对ERβ的生物学功能，变异，及其乳腺癌发生，发展，预后评估及内分泌治疗反应方面的可能作用加以综述。结果 ERβ是类固醇激素受体超家族的新成员，可能在乳腺癌发生，发展，预后评估及内分泌治疗反应方面具有重要作用。结论 ERβ是一种新的乳腺癌预后评估指标。     

Quantitative Progesterone Receptor Expression and Efficacy of Anti‐estrogen Therapy in Breast Cancer

The central role of estrogen receptor (ER) presence in predicting which breast cancer patients are likely to benefit from anti‐estrogen therapies is well‐established, but the added benefit of progesterone receptor (PR) and in particular low levels of PR is less well understood. The objective of this study was to determine the quantitative relationship between borderline levels of PR and subsequent benefit from anti‐estrogen therapy. We examined data from 447 patients, age 50 or older. ER and PR levels were quantitated by conventional ligand binding assay and Scatchard plot analysis or by enzyme‐linked immunoassay. Comparison of clinical outcome in relation with ER and PR status was calculated using Kaplan‐Meier actuarial survival analysis and the log‐rank test. Subpopulation treatment effect pattern plot (STEPP) analysis was used to explore the interaction between treatment effects and ER or PR levels for the 409 patients with ER values greater than 0. For anti‐estrogen treated patients, when the ER and PR positivity cut‐off was set at 1.0 fmole/mg protein, there was a statistically significant advantage for patients with ER+PR+ over ER+ PR? tumors for both breast cancer‐free interval (BCFI) and overall survival (OS). STEPP analysis found no overall interaction between treatment outcome (5 year survival probability) and levels of hormone receptor. However, patients with borderline PR levels did not appear to benefit from anti‐estrogen therapy. PR levels above borderline in addition to the presence of ER predicts an increased probability of benefit from anti‐estrogen therapy in breast cancer patients.