Progesterone Receptor Receptor Research Articles

Abstract PS15-06: Results of the window-of-opportunity PIONEER trial evaluating addition of the progesterone receptor (PR) agonist megestrol to letrozole for early stage estrogen receptor (ER) positive breast cancer: exploiting ER-PR interaction

Abstract Background: Pre-clinical data suggest that combining anti-estrogen treatment with a progesterone receptor agonist leads to greater inhibition of tumor proliferation, due to molecular interactions between ER and PR [1]. A high dose of the PR agonist megestrol (160mg daily) is approved as monotherapy for the treatment of ER positive metastatic breast cancer. A lower dose of megestrol (20-40mg daily) can be an effective treatment for severe hot flashes associated with endocrine therapy [2] but whether this dose has anti-tumor activity is unknown. The PIONEER trial evaluated the potential anti-proliferative effect of low and high dose megestrol in combination with letrozole, relative to letrozole alone, using a short-term preoperative ‘window’ trial design assessing the direct effects of the trial treatment on tumor tissue before and after treatment. Methods: Eligible patients were post-menopausal women with histologically confirmed ER+ (Allred ≥ 3) HER2 negative breast cancer at least 10mm in size, with an ECOG performance status ≤ 2, planned for primary surgery or endocrine therapy. Enrolled patients were randomised 2:3:3 to Arm A: letrozole alone, Arm B: letrozole + lower-dose megestrol (40mg) or Arm C: letrozole + higher-dose megestrol (160mg). Treatment was given for 15 (13-19) days prior to surgery or end of treatment (EOT) core biopsy. The primary endpoint was change in tumor proliferation between baseline and EOT in Arm A vs (Arms B+C combined), measured by Ki67 immunohistochemistry (IHC). Secondary endpoints were comparison of Ki67 change in high versus low dose megestrol arms, absolute Ki67 at EOT, and change in tumor apoptosis (cleaved caspase 3 IHC), proliferation (Aurora Kinase A IHC), PR and androgen receptor expression. Exploratory analysis of ER chromatin binding (ChIP-Seq) was conducted on paired fresh-frozen samples from a subset of patients. Results: A total of 243 patients were randomised from July 2017 to October 2022 with recruitment paused for 3 months at onset of the COVID pandemic. 198 patients completed treatment and had evaluable tissue samples at baseline and EOT (Arm A: n = 51, Arm B: n = 74, Arm C: n = 73). Baseline mean Ki67 values were well balanced. Therapy was well tolerated and adverse events ≥ grade 3 were similarly rare across arms (A: 3.3%, B+C: 3.5%). The mean % reduction in Ki67 for each arm was: Arm A (letrozole): 71%, Arm B (letrozole + 40mg megestrol): 79%, Arm C (letrozole + 160mg megestrol): 80%. There was a statistically significantly greater reduction in Ki67 with megestrol combinations (B+C) versus letrozole alone (A) (P = 0.013). Analyses of secondary IHC endpoints and ER ChIP-Seq are ongoing and will be presented. Conclusion: Addition of the PR agonist megestrol enhanced the anti-proliferative effect of letrozole in this window-of opportunity trial. Megestrol combinations were well tolerated, and the anti-proliferative effect was observed in both low and high dose arms. These data support the potential use of low-dose megestrol as an inexpensive and well-tolerated means of improving aromatase inhibitor efficacy. Low dose megestrol can also ameliorate hot flashes and therefore might be a strategy to improve both treatment adherence and clinical outcomes for patients taking adjuvant endocrine therapy.

Nandrolone treatment of adolescent female rats alters reproductive tissue and gonadal steroid profile

Anabolic androgenic steroids (AAS) are drugs that mimic the chemical structure of testosterone. The most commonly AAS used by young adults is nandrolone. In the USA, more than 20 % of AAS users started using steroids before the age of 20. This is alarming as most female users are unaware of the detrimental reproductive effects of AAS use such as amenorrhea, anovulation and clitoromegaly. An additional detrimental effect of AAS is their addictive liability. Previous studies indicate that animals self-administer AAS. Furthermore, AAS can cross-sensitize with other drugs of abuse such as cocaine. Our goal was to elucidate the effects of both AAS and cocaine in the reproductive system of female rats. Our hypothesis is that AAS will have a detrimental effect on the reproductive system of female rats. Adolescent female rats were divided into two large groups, one that received nandrolone decanoate (20mg/kg/sc) and another that received sesame oil (vehicle) for 10 successive days starting on day 28. Animals were further subdivided into groups that received saline or cocaine injections (0.01cc/10g) for a total of 4 groups: Oil-Saline, ND-Saline, Oil-Cocaine and ND-Cocaine. One cohort (Day 40) received cocaine or saline injections (0.01cc/10g) from days 40 to 44 and on days 52 and day 62. The other cohort (Day 65) received cocaine or saline injections from days 65 to 69 and on days 77 and 87. Our data show that administration of nandrolone during adolescence increased body weight of female rats. Ovarian weight was decreased, and ovarian tissue presented multiple cysts with fewer follicles. Nandrolone also disrupted uterine morphology. The uterine lumen was increased, the endometrial thickness reduced and thickness of myometrial tissue, as well as uterine weight, was increased. In addition, nandrolone reduced both endometrial estrogen and androgen receptors, an effect lost by day 88. In contrast, uterine tissue at day 63 showed an increase in progesterone receptor (PR) immunoreactivity, whereas PR immunoreactivity decreased in tissue obtained at Day 88 regardless of whether animals had received cocaine. Cocaine also increased PR receptors in uterine tissue at day 63 and 88. Animals treated with nandrolone had higher serum concentrations of testosterone and estradiol and a lower level of progesterone. These data show that nandrolone when administered in supraphysiologic doses during adolescence, has long lasting effects on the reproductive system of the female rat due to the depot effects and long half-life of this drug. These data warrant further research in this area to determine the long-term consequences of early nandrolone exposure on the female reproductive system, as well as fertility. Financial assistance was provided by the Offce of International Science and Engineering (OISE) of NSF through the Partnerships for Research and Education (PIRE) Program (OISE-#1545803). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association of hormone receptors and human epidermal growth factor receptor-2/neu expressions with clinicopathologic factors of breast carcinoma: a cross-sectional study in a tertiary care hospital, Kabul, Afghanistan

BackgroundBreast cancer (BC) is one of the major causes of death worldwide. It is the most common cause of death before the age of 70 years. The incidence and mortality of BC are rapidly increasing, posing great challenges to the health system and economy of every nation.MethodologyA cross-sectional analytical study was conducted at the Department of Pathology and Clinical Laboratory of the French Medical Institute for Mothers and Children (FMIC) to demonstrate the association of human epidermal growth factor receptor 2 (Her2/Neu) and estrogen receptor (ER)/ progesterone receptor (PR) with clinical as well as pathological parameters among women with BC. A consecutive nonprobability sampling method was used for this study over a span of one and a half years.ResultsOne hundred twenty participants diagnosed with breast cancer were included in the study. The mean age at diagnosis was 44.58 ± 11.16 years. Out of the total patients, 68 (56.7%) were above 40 years old, 108 (90%) were married, 94 (78.3%) were multiparous, and 88 (73.3%) had a history of breastfeeding. 33.3% of cases were within the age range of menopause (40–50 years). The positive expression rates of ER, PR, and Her2/neu were found to be 48.8%, 44.6%, and 44.6%, respectively, and Her2/neu overexpression was found to be higher among ER/PR-negative cases.ConclusionIn our study, we demonstrated that among Afghan women, grade II invasive ductal carcinoma, not otherwise specified, was the most common type of BC and frequently affected women above the age of 40. We also revealed that the percentage of negative ER (50.4%), negative PR (54.4%), and concordant ER/PR-negative cases were high compared to other possibilities. Additionally, the study revealed that expression of Her2/neu was in contrast with the expression of ER and PR receptors. The findings of our study still support the importance of performing immunohistochemical stains for hormonal receptor classification in terms of better clinical outcomes and prognosis.

CAMP regulates the progesterone receptor gene expression through the protein kinase A pathway during decidualization in human immortalized endometrial stromal cells

Decidualization, a crucial process for successful pregnancy establishment and maintenance, involves endometrial stromal cell differentiation. This process is orchestrated by estradiol (E2), progesterone, and other stimuli that increase intracellular cyclic adenosine monophosphate (cAMP) levels. The intracellular progesterone receptor (PR), encoded by the PGR gene, has a key role in decidualization.This study aimed to understand the role of sex steroids and cAMP in regulating PGR expression during the in vitro decidualization of the human immortalized endometrial stromal cell line, T-HESC. We subjected the cells to individual and combined treatments of E2, medroxyprogesterone (MPA), and cAMP. Additionally, we treated cells with PR and estrogen receptor antagonists and a protein kinase A (PKA) inhibitor. We evaluated the expression of PGR isoforms and decidualization-associated genes by RT-qPCR.Our findings revealed that cAMP induced PGR-B and PGR-AB expression by activating the PKA signaling pathway, while MPA downregulated their expression through the PR. Furthermore, downstream genes involved in decidualization, such as those coding for prolactin (PRL), insulin-like growth factor-binding protein-1 (IGFBP1), and Dickkopf-1 (DKK1), exhibited positive regulation via the cAMP-PKA pathway. Remarkably, MPA-activated PR signaling induced the expression of IGFBP1 and DKK1 but inhibited that of PRL.In conclusion, we have demonstrated that the PKA signaling pathway induces PGR gene expression during in vitro decidualization of the T-HESC human endometrial stromal cell line. This study has unraveled some of the intricate regulatory mechanisms governing PGR expression during this fundamental process for implantation and pregnancy maintenance.

Histopathological Patterns and Outcomes of Triple-Positive Versus Triple-Negative Breast Cancer: A Retrospective Study at a Tertiary Cancer Center.

Background One of the leading causes of cancer-related deaths in females under 45 years old is breast cancer (BC). The definition of triple-negative breast cancer (TNBC) is the lack of expression of estrogen receptors (ERs) as well as progesterone receptors (PRs) and Erb-B2 receptor tyrosine kinase 2 (HER2) gene amplification. Triple-positive breast cancer (TPBC), on the other hand, is defined as tumors expressing a high level of ER, PR, and HER2 receptors. This study aims to assess the phenotypes of TNBC and TPBC by comparing their individual clinical behavior patterns and prognosis throughout the course of the disease in a tertiary cancer center in the Kingdom of Saudi Arabia (KSA). Methods Our study is a retrospective study using electronic medical records (EMRs) to identify all female patients diagnosed with BCusing the International Classification of Diseases-10 (ICD-10) codes (between C50 and C50.9). About 1209 cases with primary BC female patients were recognized based on histopathology reports. Further subclassification into TPBC and TNBC was performed. Statistical analysis was performed using Rv3.6.2 (R Studio, version 3.5.2, Boston, MA, USA). The descriptive data were presented as means and standard deviations (SD).Survival curves were approximated using the Kaplan-Meier method. The comparison between survival curves between both groups was achieved using the log-rank test. The multivariate model was constructed based on the identified predictors using univariate analysis. Results Univariate analysis of overall survival (OS) showed that mortality was higher in TNBC compared to TPBC (HR = 2.82, P-value <0.05). However, in a multivariate analysis, molecular subtypes did not show a significant effect on OS with a P-value of 0.94. We found that age at diagnosis has been associated with a 4% increase in mortality risk with a yearly rise in age. Conclusion In this limited retrospective cohort study, we found that TNBC may not be associated with a higher risk of death than TPBC. However, other factors, including age at diagnosis, surgical intervention, and lymphovascular invasion (LVI), have been observed to increase the risk of mortality. On the other hand, patients with TNBC were found to have a worse prognosis in terms of local recurrence.This information cannot be generalized to all patients with BC given the limitations of this study. Further, larger cohorts are needed to explore biological and treatment-related outcomes in patients with TNBC and TPBC.

Clinicopathological and prognostic characteristic features of triple negative and nontriple negative breast cancer at a tertiary care hospital.

Carcinoma breast is a complex disease having diverse clinical, histopathological, and immunohistochemical features. Basing on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2) status, these tumors are divided into triple-negative breast cancers (TNBC) where tumor cells are negative for all three receptors and nontriple negative breast cancer (non-TNBC) where tumor cells are positive for one or two or all. The clinicopathological and characteristic prognostic features are highlighted here. The aim of this study is to evaluate the clinicopathological and prognostic features of TNBC and non-TNBC cases diagnosed in our hospital setting. Single institution, retrospective study conducted over 7 and half years. Histopathologically confirmed breast cancer cases with ER, PR, and HER2 receptor assessment were categorized into TNBC and non-TNBC. Detailed study on clinicopathological and prognostic features including pathological prognostic stage as per 8th AJCC was done in cases who underwent modified radical mastectomy. Data were analyzed in percentage and presented in tables and charts. The present study included 794 cases consisting of 253, 31.9% TNBC and 541, 68.1% non-TNBC cases. The mean age of TNBC and non-TNBC cases was 50.4 years and 51.7 years, respectively. Coagulative necrosis, lymphovascular invasion, lymph nodal metastasis, higher histopathological tumor grade, and NPI were observed in higher percentage of TNBC cases, i.e., 19 (10.9%), 21 (11.6%), 105 (57.7%), 127 (69.8%), and 149 (81.9%) cases, respectively, than non-TNBC seen in 18 (6.6%), 24 (8.8%), 135 (49.6%), 165 (60.7%), and 194 (71.3%) cases, respectively. Further, 25 (13.7%) TNBC and 1 (0.4%) non-TNBC case were upstaged, whereas 130 (47.8%) non-TNBC and 2 (1.1%) TNBC cases were downstaged by the pathological prognostic stage. TNBC is more aggressive having a poor prognosis than non-TNBC.

Activation of progesterone receptor is essential for folic acid-regulated cancer cell proliferation and migration

We previously demonstrated that activation of progesterone receptor (PR) is essential for folic acid (FA)-inhibited proliferation in colorectal cancer cell lines. In the present study, we further investigated whether the requirement of PR activation for the FA-regulated cell proliferation and migration is a general phenomenon for all cancer cell lines or specific for colorectal cancer cell lines only. Initially, we examined the expression of PR in various cancer cell lines using Western blot analyses and RT-PCR technique, and then investigated the effects of FA on these cancer cell lines. Our data showed that the effects of FA on proliferation and migration only occurred in the PR positive (+) cancer cell lines, but not the PR negative (-) cancer cell lines, and these effects were abolished by pre-treatment with the PR specific inhibitor, Org 31710. On the other hand, FA significantly reduced the proliferation and migration in the PR (-) cancer cell lines transfected with PR pcDNA. However, FA did not significantly affect the proliferation and migration in the PR-transefected Hep-3B cell line, which does not express endogenous PR and FA receptor (FR). Since we previously showed that FA-regulated proliferation in colorectal and breast cancer cell lines through the cSrc-mediated pathway, we conducted immunoprecipitation assay to demonstrate that PR formed a complex with FR and cSrc, but FR did not directly associate with cSrc. Taken together, these findings suggest that the requirement of PR activation for the FA-regulated cell proliferation and migration is a general phenomenon for all cancer cell lines.

Molecular Classification of Breast Carcinoma in a Tertiary Hospital of India: the Recent Trends.

Breast cancer is a heterogeneous disorder with various subcategories of different cellular compositions, molecular alterations, and clinical behaviour and is dependent on numerous factors like grade, size, and hormonal receptors which influence the overall prognosis and response to the treatment. This study was done to determine the frequency of estrogen receptor (ER), progesterone receptor (PR), and Her2 neu positivity in breast cancer patients, further classifying them into their molecular types (luminal A, B, Her2 neu, and triple-negative) and studying their association with histological subtypes, lymph node status, and other epidemiological parameters. This was a 5-year retrospective study done on 314 patients. All relevant clinical data including the age, sex, and lymph node status along with the histological type and grade of the tumour were recorded, and immunohistochemical evaluation of Her2 neu, ER, and PR receptors was done. The results showed that ER was the most predominant immunomarker, followed by PR, with an inverse relationship between ER, PR, and Her2 neu. Among the molecular subtypes, luminal B showed the maximum prevalence followed by triple-negative and Her2 neu subtype. The least frequency was shown by luminal A. Our study concluded that molecular subtyping of breast carcinoma plays an important role in determining the prognosis, recurrence, and treatment. Increased expression of luminal B subtype can be correlated due to the advancing age of the patients.

Abstract P1-02-06: Prediction of Prosigna® breast cancer intrinsic subtype by immunohistochemical ER, PR and Ki67 expression

Abstract The present study evaluated whether Prosigna® breast cancer assay intrinsic subtype (IST) can be predicted using a specified cutoff for Ki67 proliferation index and immunohistochemical (IHC) biological subtype estimation, complemented by estrogen receptor (ER) and progesterone receptor (PR) expression in a clinical cohort. Our study included 185 cases of early stage ER-positive, HER2-negative breast cancer treated at the Comprehensive Cancer Center of the Medical University of Vienna between 2014 and 2019. Prosigna® breast cancer assay was performed when recommended by the institutional multidisciplinary tumor board to aid adjuvant therapy decision. Pathological diagnostics was carried out according to current WHO and EU breast cancer screening and diagnostics guidelines. Immunohistochemical assessment of ER, PR, human epidermal growth factor receptor 2 (HER2) and proliferation index by Ki67 was performed using Ventana Benchmark Ultra (Tucson, AR, USA) according to recent ASCO/USCAP guidelines. Univariable logistic regression was used to verify that Ki67 positivity is predictive for IST LumA and LumB tumors according to Prosigna® IST. Probability for luminal B IST was estimated by receiver operating characteristics and Youden index was calculated. Next, multivariable logistic regression was applied to test the hypothesis that additional inclusion of ER and PR receptor expression contain additional information regarding IST. Median age of patients was 56 years. 52 patients (28%) had tumors larger than 2 cm (pT2-pT3). 75 patients (41%) had lymph node metastases. 83 (45%), 98 (53%) and 3 (2%) of tumors were diagnosed as luminal A, luminal B and HER2-enriched subtype by Prosigna®, respectively. 19 (10%), 77 (42%) and 89 (48%) tumors could be allocated in the low, intermediate and high risk groups, respectively. Univariable logistic regression confirmed that higher Ki67 positivity significantly, yet insufficiently predicts luminal B tumor subtype (p&amp;lt;0.0001). There was no justification for an optimal Ki67 cutoff and irrespective of its value, no more than 70% of tumors could correctly be assigned to the IST, according to a Youden-Index of maximum 0.42. The hypothesis that including ER and PR expression improves accuracy could not be confirmed (p=0.14). Although higher Ki67 positivity significantly predicted luminal B tumor subtype, the Prosigna® breast cancer assay provided independent information for adjuvant therapy decision in cases where Ki67 IST estimation alone is not sufficient. Irrespective of the chosen cutoff value, a maximum accuracy of 70% was achieved for correctly predicting IST, including ER and PR expression into our model did not improve accuracy. Therefore, IST determination by the Prosigna® breast cancer assay cannot be replaced by immunohistochemical parameters. Citation Format: Ulrike Heber, Kristina Tendl-Schulz, Stefan Heber, Sabine Danzinger, Rupert Bartsch, Christian F. Singer, Florian Fitzal, Ruth Exner, Michael F. Gnant, Leonhard Müllauer, Zsuzsanna Bago-Horvath. Prediction of Prosigna® breast cancer intrinsic subtype by immunohistochemical ER, PR and Ki67 expression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-06.

Steroid Receptor Coregulators Can Modulate the Action of Progesterone Receptor during the Estrous Cycle in Cow Endometrium.

Simple SummaryProper functioning of the endometrium is necessary for the implantation of the embryo after fertilization and its development throughout pregnancy. The key role in this process plays appropriate action of progesterone through the nuclear receptor isoforms. The action of the receptor is regulated by the attachment of receptor modulators called coregulators which include coactivators and corepressors. Their improper expression in humans causes a malfunction of progesterone receptors and leads to disorders of pregnancy. However, in farm animals, such disorders may be one of the reasons leading up to early embryonic lethality, which in cows reaches up to 40%. Obtained results indicate the important role of the studied coregulators in regulating progesterone activity in endometrial cells, especially during the preimplantation period. Therefore, they can be helpful in better understanding the regulation and expression of the coactivators and corepressors in cow endometrium during the estrous cycle and can contribute to reducing this problem. They can also be of significant practical importance, making for the increased efficiency of breeding these animals.Nuclear receptor coregulators include coactivators and corepressors which associate with the progesterone receptor (PGR) during its activation. Fluctuations in the transcription levels of their respective genes and subsequent protein production as well as in related activities for histone acetyltransferase (HAT) and histone deacetylase (HDAC) can affect PGR function and thus change the action of progesterone (P4) in bovine endometrium during the estrous cycle. Endometrial tissue on days 2–5, 6–10, 11–16, and 17–20 of the estrous cycle was used for determination of the mRNA expression levels of coactivators P300, CREB, and SRC-1 along with corepressor NCOR-2 using Real-Time PCR, with protein levels by Western blot. Coregulators cellular localizations were assessed by immunohistochemistry whereas the activities of HAT and HDAC by using EIA. The highest levels of mRNA and proteins for all of the investigated coregulators, as well as the highest levels of activity for HAT and HDAC, were detected over days 2–16 of the estrous cycle. All of the tested coregulatory proteins were localized in the nuclei of endometrial cells. This research indicates the important role of coregulators of the PGR receptor in regulating P4 activity in endometrial cells, especially during the pre-implantation period.

Crosstalk between progesterone receptor membrane component 1 and estrogen receptor α promotes breast cancer cell proliferation

Progesterone (P4) and estradiol (E2) have been shown to stimulate and regulate breast cancer proliferation via classical nuclear receptor signaling through progesterone receptor (PR) and estrogen receptor α (ERα), respectively. However, the basis of communication between PR/ERα and membrane receptors remains largely unknown. Here, we aim to identify classical and nonclassical endocrine signaling mechanisms that can alter cell proliferation through a possible crosstalk between PR, ERα, and progesterone receptor membrane component 1 (PGRMC1), a membrane receptor frequently observed in breast cancer cells. While P4 and E2 treatment increased cell proliferation of ER+/PR+/PGRMC1 overexpressing breast cancer cells, silencing ERα and PR or treatment with selective estrogen receptor modulator (SERM) tamoxifen, or (PR-antagonist) RU-486 decreased cell proliferation. All four treatments rapidly altered PGRMC1 mRNA levels and protein expression. Furthermore, P4 and E2 treatments rapidly activated EGFR a known interacting partner of PGRMC1 and its downstream signaling. Interestingly, downregulation of ERα by tamoxifen and ERα silencing decreased the expression levels of PGRMC1 with no repercussions to PR expression. Strikingly PGRMC1 silencing decreased ERα expression irrespective of PR. METABRIC and TCGA datasets further demonstrated that PGRMC1 expression was comparable to that of ERα in Luminal A and B breast cancers. Targeting of PR, ERα, and PGRMC1 confirmed that a crosstalk between classical and nonclassical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors.

Salicin a promising ER, PR and HER2 binding molecule proving lethal against Hormone + and triple negative breast cancer cells

Therapeutics against breast cancer is a major research field, due to inefficiency or partial efficiency of existing therapeutics. An urge to discover better therapeutics always persists. Our objective is to study salicin against breast cancer cells, in order to find its therapeutic properties. To study the effect of salicin on breast cancer cells, we performed MTT assay on MCF-7 (hormone positive) and MDA-MB-231 (triple negative) breast cancer cell lines, we did brine shrimp lethality test (BSLT) assay to see the lethal effects of salicin. By the help of bioinformatics we tried to locate the targets that delineate salicin activity. Salicin was docked with estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) to study its binding efficiency and possible targets of salicin. Salicin remarkably reduces cell viability both in MCF-7 and MDA-MB-231, along with being lethal to brine shrimps. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum energy required for binding. This explains that salicin can easily bind to these receptors. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum binding energy. ER, PR and HER2 are major reasons behind the disease pathogenicity depending on the type of breast cancer. According to our results salicin may either induce apoptosis or reduce cellular mitosis both via P53 dependent and independent pathway, which makes salicin a good choice of both hormone positive and negative breast cancer cells.

The Value Of Immunohistochemical Expression Of Estrogen Receptor And Progesterone Receptor Receptors In The Prognosis Of Iraqi Women With Breast Carcinoma

Background: The basic microscopical structure of the adult female breast is composed primarily of two components. The first is an active adipocyte (mesenchyme). The second is an epithelial bilayer, which is supported by Cooper ligaments (a loose framework of dense fibrous connective tissue). Immunohistochemical evaluation of breast tissue is of diagnostic, prognostic, and therapeutic relevance. Estrogen receptor (ER) and progesterone receptor (PR) are playing a vital role in the management of breast cancer because they predict response to endocrine treatment; however, they have a little prognostic role regarding the fate of disease. These receptors had assessed by immunohistochemistry (IHC) that had performed on paraffin tissue preparations. Aim of the study: The current study was aiming at highlighting the value of immunohistochemical expression of ER and PR receptors in the prognosis of Iraqi women with breast carcinoma. Materials and methods: The current study was carried out at the central laboratory of Al-Diwaniyah teaching hospital and several private histopathology laboratories in Al-Diwaniyah province, the mid-Euphrates region of Iraq. The study was started in July 2019 and ended in February 2020. Thirty-paraffin sections of breast carcinoma had retrieved from these laboratories. One-section had been made from each paraffin block and stained by the conventional hematoxylin and eosin (H and E) stain. Then, the sections had reviewed by two pathologists, who confirmed the diagnosis, as well as the other related histological features like grade, histological subtype, stromal invasion, and lymphatic and neural permeation. Two-further sections had made for immunohistochemical staining with ER and PR receptor stains. Results: The immunohistochemical expression of ER and PR receptors was as following: Positive ER only cases were 3 (10.0 %), positive PR only cases were 4 (13.3 %), and the cases which were positive for both ER and PR were 15 (50.0 %). The Cases that were negative for both ER and PR accounted for 8 (26.7 %). Total cases expressing ER accounted for 18 (60.0 %), and the cases that express PR had accounted for 19 (63.3 %). Conclusion: The immunohistochemical expression of ER and PR receptors is heterogeneous concerning the proportion and intensity of staining, and this may explain the variation of breast cancer cases in response to hormonal therapy.

Comparative Analysis of Immunohistochemistry of Hormone Receptors in Breast Cancer by Conventional and Microwave Tissue Processing Methods

Introduction: Rapid histopathological processing of neoplastic biopsies is crucial for initiating early therapy in patients. Microwave processing shortens the time to diagnosis and is less labour intensive. Aim: To compare the quality of immunohistochemical staining of Estrogen Receptors (ER) and Progesterone Receptors (PR) on paired breast samples using microwave processing versus conventional processing. Materials and Methods: A cross-sectional study was conducted at a tertiary care hospital in Kerala, India, from February 2014 to September 2015. A total of 44 paired samples from breast carcinoma patients were taken. Baseline characteristics of the patients such as age and type of carcinoma were noted. Haematoxylin and Eosin (H&amp;E) stain was used. One slide of the pair was processed conventionally and the other using a microwave. The stained slides were observed by three pathologists. The validity of ER and PR receptor status was evaluated with sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV). Kappa statistics and Spearman’s correlation test was used to denote the agreement between them. Results: The mean age was 51.32±11.16 years. There was agreement (Cohen k=0.902) between the microwave processed and conventionally processed paired breast samples for ER. The sensitivity and specificity of microwave processing in ER evaluation was 87.5% and 100% while that of PR evaluation was 92.9% and 100% respectively. The PPV was 100% and NPV was 93.3% for ER evaluation by microwave processing. Conclusion: Microwave aided tissue processing had significant advantages over conventional methods for providing a rapid diagnosis, being less laborious and had effective staining, which makes it a better choice.

Immunohistochemical Expression of BRCA1 Protein, ER, PR and Her2/neu in Breast Cancer: A Clinicopathological Study.

Breast cancer is a heterogeneous hormone-dependent disease. Potential prognosis depends on the clinicopathological evaluation and assessment of other prognostic indicators. The detection of the oestrogen Receptor (ER), Progesterone Receptor (PR), Human epidermal growth factor receptor 2 (Her2/neu) and BRCA1 oncoprotein is pivotal for prognostic evaluation and to choose the appropriate post-surgical adjuvant therapy beside selecting the proper candidate for genetic counselling. Objectives:To detect the immunoexpression of the BRCA1 oncoprotein in mammary invasive ducal carcinoma and its association with the prognostic markers (ER, PR and Her2/neu hormonal receptors) and other clinicopathological parameters to improve the patients’ treatment plans. Methods:A cross-sectional study design including 83 paraffin blocks and histological slides collected from Al-Jumhoori Medical City Teaching Hospital Laboratory in Mosul and the Central Public Health Laboratory in Baghdad between the 1st of January 2010 to the 13th of March 2012 for patients diagnosed with primary invasive ductal breast carcinomas. Immunohistochemistry (IHC) using monoclonal antibodies against ER, PR, Her2/neu receptors and BRCA1 protein was performed via the fully automated immunostaining instrument ‘Ventana Benchmark’. Results:BRCA1 protein immunoexpression was detected in 20.5% of cases. It was significantly high with increasing tumour grade and stage. Although there was a trend of BRCA1 negativity toward negative ER, PR and Her2 receptors, no significant associations were observed with any of these parameters and the patients’ age. Conclusion:Altered BRCA1 expression is significantly associated with advanced tumour grade and stage. High number of cases with negative BRCA1 expression showed negative ER, PR and Her2/neu expression.

Quantitative mast cell analysis and hormone receptor study (ER, PR and HER2/neu) in invasive carcinoma of breast.

Breast cancer constitutes nearly one third of cancers among women. Immune responses caused by neoplastic cells lead to the accumulation of inflammatory cells like mast cells (MCs), macrophages, lymphocytes, and plasma cells around the tumor tissue forming the tumor microenvironment. The study aims at quantifying the role of MCs in different grades of invasive carcinoma of breast with respect to estrogen receptor (ER), progesterone receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2/neu). This study included 60 cases of invasive carcinoma of breast. Toluidine blue staining was used for quantitative MC analysis and correlated with immunohistochemistry analysis for hormonal markers' positivity-ER, PR and HER2/neu. The mean age was 52 years (range: 25-75 years). The average number of MCs in Grade I, II, and III were 24.05, 18.4, and 7.9, respectively, with a significant P value. ER, PR, and HER2/neu positivity was found in 60%, 55%, and 32% of the cases, respectively. ER positivity with mean MC count of 23.55 was found in 36 cases, and 33 cases were positive for PR with a mean MC count of 24.18 and a significant P value. HER2 positive cases were 28 with a mean MC count of 20.82. The presence of MCs in breast cancer is inversely proportional to the grade of tumor, i.e., a maximum number of MCs were seen in low grade tumors. In addition, there is a positive correlation between ER and PR receptor positivity with the presence of MCs in the stroma of breast cancer.

Association of DEAR1 Tagging Single Nucleotide Polymorphisms With Breast Cancer in a Sample of Colombian Population: A Case Control Study.

Purpose:Ubiquitin ligase genes can act as oncogenes or tumor suppressor genes. They play a role in various diseases, including development and progression of breast cancer; the objective of this study was to evaluate the association of common variants in the ductal-epithelium-associated RING chromosome 1 (DEAR1) gene with breast cancer risk in a sample of Colombian population.Methods:We carried out a case-control study to investigate associations of variants in DEAR1 with breast cancer in women from Colombia. Single nucleotide polymorphisms (SNPs) rs584298, rs2927970, rs59983645, and rs599167 were genotyped in 1022 breast cancer cases and 1023 healthy controls using the iPLEX® and Kompetitive Allele Specific PCR (polymerase chain reaction) (KASP) method. The associations between SNPs and breast cancer were examined by conditional logistic regression. The associations between SNPs and epidemiological/histopathological variables were examined by multinomial logistic regression.Results:Associations were found between tag SNPs and breast cancer adjusted for the epidemiological risk factors rs584298 genotypes AG and GG (P = .048 and P = .004, respectively). The analysis of the disease characteristics showed that SNP rs584298 (genotype AG) (P = .015) shows association with progesterone receptor (PR) status and (genotype AA) (P = .048) shows association with human epidermal growth factor receptor 2 (HER2) status.Conclusions:The SNP rs584298 in DEAR1 showed associations with breast cancer and the expression of HER2 receptor; when this receptor is amplified, the result is aggressive tumoral subtype and expression of PR receptor that is associated with high-proliferative tumor grade. Validation of this SNP is important to establish whether this variant or the tagged variant is the cause for the risk association showed.

Abstract 1585: Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone

Abstract BACKGROUND: Progesterone is a proliferative hormone in the breast. Combined estrogen plus progestin use in postmenopausal women increases mammographic density; a very strong risk for breast cancer. Circulating progesterone and genetic variations in progesterone receptor (PGR)-related genes are positively associated with mammographic density in postmenopausal women, but there are limited data in premenopausal women, with conflicting results. Notably, besides hormone therapy, genetic variation in PGR genes are known to modulate circulating progesterone levels. We, therefore, investigated the associations of genetic variations in PGR-related genes (PGR and Progesterone Receptor Membrane Component 1 (PGRMC1) with mammographic density in premenopausal women and determine, for the first time, whether these associations are mediated via circulating progesterone. METHODS: We genotyped 179 PGR-related single nucleotide polymorphisms (SNPs) (155 for PGR and 24 for PGRMC1 - 17 of which were synonymous variants and were filtered) in 364 cancer-free premenopausal women who had screening mammography at the Joanne Knight Breast Health Center at Washington University School of Medicine, St. Louis in 2016. We used Volpara to determine volumetric percent density, and dense volume. Variants were coded in dominant mode of inheritance. For causal mediation analysis, multivaraite linear regression models were applied to both the mediator (circulating PGR in logarithm scale) with variants and volumetric percent density, and dense volume with variant, PGR in logarithm scale and their interaction, both adjusting for age, body mass index, family history of breast cancer, and parity. The causal mediation effect, direct effect and total effect, by gentoype and averaged across genotypes were estimated with 95% confidence intervals and p values. Significance was claimed with p-value≤0.05. RESULTS: The mean age of the study participants was 47.5 years. Most participants (42.1%) had volumetric percent density between 3.5-7.5%, equivalent to BI-RADS® category b. Rs2020875 (PGR11) had a positive average direct effect (estimate=0.22, 95% CI, 0.016~0.44, p-value=0.024) and rs645213 (PGR11) had a borderline inverse direct effect (-0.25, -0.48~0.0004, p-value=0.052) on volumetric percent density. Further, rs11224565 (PGR11): 0.19, 0.04~0.34, p-value=0.028 had positive average direct effects on dense volume. None of the mediation effects were statistically signficiant. CONCLUSIONS: SNPs in PGR-related genes are associated with mammographic density in premenopausal women. Circulating progesterone levels did not mediate the associations between variants in PGR-related genes and mammographic density. Larger studies are needed to confirm our findings. Citation Format: Favour A. Akinjiyan, Yunan Han, Jingqin R. Luo, Aldi Kraja, Catherine M. Appleton, Graham A. Colditz, Adetunji T. Toriola. Genetic variations in progesterone receptor (PGR)-related genes and mammographic density in premenopausal women: Are the associations mediated by circulating progesterone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1585.

Aromatase CYP19A1, progesterone receptor PGR and estrogen receptor ESR1 gene expression in biopsy specimens of endometrioid heterotopia and endometrial tissue by reverse transcription PCR

Hypothesis/aims of study. Endometriosis is one of the most pressing problems of gynecology. Clarifying the expression of the estrogen receptor (ESR1) and the progesterone receptor (PGR) genes and polymorphisms in the aromatase (CYP19A1) gene in endometriosis will expand the understanding of the pathogenesis of the disease and the causes of resistance to its therapy. The objective of this study was to conduct a comparative analysis of mRNA expression of PGR, ESR1 and CYP19A1 genes in paired samples of the eutopic endometrium and peritoneal endometrioid lesions in order to search for predictive markers of response to hormonal therapy. In the future, this may allow personalizing the selection of hormonal preparations for the treatment of endometriosis.&#x0D; Study design, materials and methods. Reverse transcription real-time PCR made it possible to evaluate CYP19A1, PGR and ESR1 gene expression levels in studied tissue samples from 22 patients with endometriosis and 9 women in the comparison group.&#x0D; Results. Quantitative analysis revealed a high heterogeneity in the expression level of the studied genes, in both the endometrium and endometrioid lesions from patients with endometriosis. In the endometrium of patients in the comparison group, the heterogeneity of the expression level was observed only for the ESR1 gene.&#x0D; Conclusion. Our findings suggest a high variability in CYP19A1, ESR1 and PGR gene expression levels in the endometrium and peritoneal foci in patients with endometriosis. This information indicates the need for an individual approach to prescribing targeted therapy, since it is obvious that the effect of treatment will depend primarily on the availability of a therapeutic target in a particular patient. The absence of a typical expression pattern for each of the genes in patients with endometriosis indicates the heterogeneity of the disease and the need to develop a molecular classification of this common pathology.

Receptor status conversion between primary and recurrent/metastatic breast cancer: A single institutional study.

e14735 Background: Hormone receptor and HER2 status have both predictive and prognostic implications in breast cancer (BC). Studies report differences of 3% to 54% for Estrogen receptor (ER), 5% to 78% for Progesterone receptor (PR), and 0% to 34% for HER2 between primary (P) and recurrent/metastatic breast cancer (RMBC). To evaluate this difference, we conducted an observational single institution study in adult patients (pts) ≥ 18 years with RMBC. Methods: After IRB approval, we conducted a retrospective chart review of pts diagnosed with RMBC between January 1st, 2010 and October 31st, 2018, with history of PBC. We recorded age at PBC diagnosis, stage, tumor type, receptor status, initial treatment, age at RMBC diagnosis, if biopsy performed, receptor status and survival. We studied the differences in ER, PR and HER2 receptors between P and RMBC. Descriptive statistics was used for analysis. Results: We found a total of 179 pts in the time interval. Median age was 54 ± 13.2 years at PBC diagnosis, 98.9% females, 1.1% males. 187 events were recorded. At PBC diagnosis, 27.4% had Stage I, 37.4% had Stage II and 31.8% had Stage III disease. Tumor type was ductal in 83.8% and lobular in 12.2%. 78.8% was ER+, 68.7% was PR+ and 14% was HER2+. 70.9% received chemotherapy, 12.8% received HER2 therapy and 67% received hormonal therapy. Age at RMBC was median of 61 ± 13.1 years. Biopsy was done in 93.3%. Time between PBC and RMBC ranged from 7 and 324 months. 31.3% had local recurrence and 68.7% had distant disease. In RMBC, 59.2% was ER+, 41.9% was PR + and 13.4% was HER2 +. 58.7% are alive and 38% deceased. With RMBC, 19.2% who were ER+ became ER-, 4.9% who were ER- became ER+, 37.5% who were PR+ became PR-, 8.6% who were PR- became PR+, 23.1% who were HER2+ became HER2-, 4.5% who were HER2 - became HER2+. In pts who became ER-/PR-, 88.5% received hormonal therapy and 61.5% received chemotherapy at the time of PBC. In pts who became HER2-, 83.3% received HER2 therapy at the time of PBC. Conclusions: In our study, we found a difference of 24.1% in ER, 46.1% in PR and 27.6% in HER2 between PBC and RMBC. It is recommended that patients with RMBC should have a biopsy to evaluate the receptor status as it would impact treatment and survival.