Progesterone Receptor Expression Status Research Articles

Transcriptomic Profile of Breast Tissue of Premenopausal Women Following Treatment with Progesterone Receptor Modulator: Secondary Outcomes of a Randomized Controlled Trial.

Progesterone receptor antagonism is gaining attention due to progesterone's recognized role as a major mitogen in breast tissue. Limited but promising data suggest the potential efficacy of antiprogestins in breast cancer prevention. The present study presents secondary outcomes from a randomized controlled trial and examines changes in breast mRNA expression following mifepristone treatment in healthy premenopausal women. We analyzed 32 paired breast biopsies from 16 women at baseline and after two months of mifepristone treatment. In total, 27 differentially expressed genes were identified, with enriched biological functions related to extracellular matrix remodeling. Notably, the altered gene signature induced by mifepristone in vivo was rather similar to the in vitro signature. Furthermore, this gene expression signature was linked to breast carcinogenesis and notably linked with progesterone receptor expression status in breast cancer, as validated in The Cancer Genome Atlas dataset using the R2 platform. The present study is the first to explore the breast transcriptome following mifepristone treatment in normal breast tissue in vivo, enhancing the understanding of progesterone receptor antagonism and its potential protective effect against breast cancer.

Progesterone-Cationic Lipid Conjugate-Based Self-Aggregates for Cancer Cell-Selective Uptake through Macropinocytosis and the Antitumour Effect.

Progesterone (PR) is an endogenous steroid hormone that activates the progesterone receptor (PgR) and is known to play a critical role in cancer progression. Herein, we report the development of cationic lipid-conjugated PR derivatives by covalently conjugating progesterone with cationic lipids of varying hydrocarbon chain lengths (n = 6-18) through a succinate linker. Cytotoxicity studies performed on eight different cancer cell lines reveal that PR10, one of the lead derivatives, exerts notable toxicity (IC50 = 4-12 μM) in cancer cells irrespective of their PgR expression status and remains largely nontoxic to noncancerous cells. Mechanistic studies show that PR10 induces G2/M-phase cell cycle arrest in cancer cells, leading to apoptosis and cell death by inhibiting the PI3K/AKT cell survival pathway and p53 upregulation. Further, in vivo study shows that PR10 treatment significantly reduces melanoma tumor growth and prolongs the overall survival of melanoma tumor-bearing C57BL/6J mice. Interestingly, PR10 readily forms stable self-aggregates of ∼190 nm size in an aqueous environment and exhibits selective uptake into cancerous cell lines. In vitro uptake mechanism studies in various cell lines (cancerous cell lines B16F10, MCF7, PC3, and noncancerous cell line HEK293) using endocytosis inhibition proves that PR10 nanoaggregates enter selectively into the cancer cells predominantly using macropinocytosis and/or caveolae-mediated endocytosis. Overall, this study highlights the development of a self-aggregating cationic derivative of progesterone with anticancer activity, and its cancer cell-selective accumulation in nanoaggregate form holds great potential in the field of targeted drug delivery.

A systematic literature review of prognostic factors in patients with HR+/HER2- advanced breast cancer in Japan.

BackgroundBreast cancer is the most prevalent cancer in women in Japan and the fifth in mortality. This systematic review summarized the evidence for prognostic factors for patients with HR+/HER2− advanced and metastatic breast cancer in Japan.MethodsMEDLINE and EMBASE were searched with keywords ‘breast neoplasms’ AND ‘Japan’ AND ‘advanced’ or equivalent, and Japan Medical Society database with ‘breast cancer’ AND ‘advanced/metastatic’ for publications from January 2010 to October 2019. ASCO, ESMO, ABC4 abstracts and WHO website were hand searched. The endpoints of interest were overall survival, progression-free survival, tumour response and post-progression survival. Factors were evaluated based on the consistency in direction and the strength (hazard ratios) of association.ResultsSearches identified 4530 publications, of which 27 were eligible. All were observational studies. Among the endpoints, overall survival was the most commonly assessed (n = 22) and evaluated further. Ki-67 expression, progesterone receptor expression status, tumour grade and lymph node metastases were consistently associated with poor overall survival in univariate analysis but not in multivariate analysis. Short disease-free interval, the number of metastatic organs and liver metastasis were consistently associated with poor overall survival in both of univariate and multivariate analysis. The association was strong for liver metastasis (hazard ratio ≥2.8 in the majority of studies) and moderate for disease-free interval and the number of metastatic organs (hazard ratio 1.3–2.8 in the majority of studies).ConclusionsDisease-free interval, the number of metastatic organs and liver metastasis were identified as independent prognostic factors for overall survival. These findings may help clinical decision-making to improve outcomes in patients with HR+/HER2− advanced and metastatic breast cancer.

Tumour-infiltrating CD4-, CD8- and FOXP3-positive immune cells as predictive markers of mortality in BRCA1- and BRCA2-associated breast cancer.

The prognostic value of tumour-infiltrating lymphocytes (TILs) in breast cancer is well-established. However, the investigation of specific T-cell subsets exclusively in BRCA-associated breast cancer is sparse. Tumour tissues from 414 BRCA-mutated breast cancer patients were analysed by immunohistochemistry and digital image analysis for expression of CD4, CD8 and FOXP3 immune markers. Distribution of CD4-, CD8- and FOXP3-positive cells and clinicopathological characteristics were assessed according to groups of low or high expression. The prognostic value was evaluated as continuous variables in univariate and multivariate analyses of overall survival and disease-free survival. Both CD4 and CD8 expression are associated with histological diagnosis, tumour grade and oestrogen and progesterone receptor expression status. CD4 expression is associated with BRCA gene status. A high percentage of tumour-infiltrating CD4-, CD8- or FOXP3-positive cells is significantly associated with lower mortality in BRCA1- and BRCA2-associated breast cancer and CD8-positive cells areassociated with disease-free survival. No heterogeneity according to BRCA gene status was found for the prognostic value of the immune markers. The results support a prognostic role of specific T-cell subsets in BRCA-associated breast cancer and the promising potential of targeting the immune system in the treatment of these patients.

Evaluation of Expression and Phosphorylation of Progesterone Receptor in Endometrial Stromal Cells of Patients with Recurrent Implantation Failure Compared to Healthy Fertile Women

Recurrent implantation failure (RIF) is the repeated failure of good-quality embryos in implantation process following several assisted reproduction cycles. Disruption of the endometrial receptivity is one of the main causes of RIF. Progesterone plays a pivotal role in the endometrial receptivity through the regulation of gene expression pattern by binding to its receptors in the endometrial cells. The aim of this study was to evaluate the expression level of progesterone receptor (PR) and its phosphorylated form in the endometrial stromal cells (eSC) of RIF patients and compare it to the eSC of healthy fertile women as control group. After isolation of the eSC from biopsy samples of RIF patients and healthy fertile women and their characterization, expression levels of PR mRNA, PR protein, and phospho-Ser294 PR protein were evaluated by quantitative real-time PCR and immunofluorescence staining, respectively. The results demonstrated a significant reduction in PR mRNA expression (P < 0.01.) and phospho-Ser294 PR protein (P < 0.05) level in RIF patients compared to the control group. These data for the first time suggest that the expression of PR and its phosphorylated form are impaired in RIF patients. Therefore, designing therapeutic methods for improving PR expression status and its regulation in the endometrium of RIF patients may help in improving the final reproductive outcomes of these cases.

Metformin regulation of progesterone receptor isoform-B expression in human endometrial cancer cells is glucose-dependent.

Metformin (MET) constitutes the first-line treatment against type 2 diabetes. Growing evidence linking insulin resistance and cancer risk has expanded the therapeutic potential of MET to several cancer types. However, the oncostatic mechanisms of MET are not well understood. MET has been shown to promote the expression of progesterone receptor (PGR) and other antitumor biomarkers in patients with non-diabetic endometrial cancer (EC) and in Ishikawa EC cells cultured in normal glucose (5.5 mM) media. Therefore, the present study aimed to assess the effects of MET on EC cells under conditions simulating diabetes. Ishikawa cells treated with 10 nM 17β-estradiol (E2) and/or 100 µM MET and exposed to normal and high (17.5 mM) concentrations of glucose were evaluated for proliferative and PGR expression status. Under normal glucose conditions, MET attenuated E2-induced cell proliferation and cyclin D1 gene expression, and increased total PGR and PGR-B transcript levels. MET inhibited Ishikawa cell spheroid formation only in the absence of E2 treatment. In E2-treated cells under high glucose conditions, MET showed no effects on cell proliferation and spheroid formation, and increased total PGR but not PGR-B transcript levels. Transfection with Krüppel-like factor 9 small interfering RNA increased PGR-A transcript levels, irrespective of glucose environment. Medroxyprogesterone acetate downregulated PGR-A expression more effectively with metformin under high compared with normal glucose conditions. To evaluate the potential mechanisms underlying the targeting of PGR by MET, E2-treated cells were incubated with MET and the AMPK inhibitor Compound C, or with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), under normal glucose conditions. Compound C abrogated the effects of MET on PGR-B while AICAR increased PGR-B transcript levels, albeit less effectively compared with MET. The present results demonstrate the glucose-dependent effects of MET on PGR-B isoform expression, which may inform the response to progestin therapy in diabetic women with EC.

Analysis of the prognostic relevance of sex-steroid hormonal receptor mRNA expression in muscle-invasive urothelial carcinoma of the urinary bladder.

Muscle-invasive urothelial carcinoma of the urinary bladder (UCB) often recurs following radical cystectomy (RC). An altered expression of sex-steroid hormone receptors has been associated with oncological outcomes of UCB and may represent therapeutic targets. Here the expression of different hormone receptors was measured on mRNA levels in patients treated by RC and associated with outcomes. Androgen receptor (AR), estrogen receptor 1 (ESR1), and progesterone receptor (PGR) mRNA expression was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in RC samples of 87 patients with a median age of 66 (39-88) years. Univariate and multivariate analyses were performed to test associations with pathological and clinical characteristics as well as recurrence-free (RFS) and disease-specific survival (DSS). AR mRNA expression was lower in comparison with ESR1 and PGR expression (p < 0.0001). In univariate analysis, high expression levels of AR were associated with reduced RFS (HR 2.8, p = 0.015) and DSS (HR 2.8, p = 0.010). High AR mRNA expression and a positive lymph node status were independent predictors for reduced RFS (HR 2.5, p = 0.0049) and DSS (HR 3.4, p = 0.009). In patients with low AR mRNA expression, an increased ESR1 and PGR mRNA expression were associated with reduced RFS and DSS. High expression levels of AR are significantly associated with adverse outcome in patients with muscle-invasive UCB following RC. ESR1 and PGR expression status can further stratify patients with low AR expression into subgroups with significantly reduced RFS and DSS. Therapeutic targeting of AR may influence outcomes in patients with UCB.

Association of neutrophil/lymphocyte ratio and platelet/lymphocyte ratio with ER and PR in breast cancer patients and their changes after neoadjuvant chemotherapy.

Proinflammatory markers, including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), are associated with many aspects of different malignancies. The aim of this study was to assess the associations of NLR and PLR with estrogen receptor (ER) and progesterone receptor (PR) expression in locally advanced breast cancer patients and their changes after neoadjuvant chemotherapy (NAC). Whether these parameters were predictive for the response to NAC in breast cancer patients was also evaluated. 132 Female primary locally advanced breast cancer patients treated with either ET (epirubicin-docetaxel), TEC (docetaxel-epirubicin-cyclophosphamide), or CEF (cyclophosphamide-epirubicin-fluorouracil) as NAC were retrospectively studied. NLR and PLR were calculated from peripheral blood cell count and their optimal cutoff levels were determined by receiver operating characteristic curves. The proportion of ER-positive breast cancers before NAC was higher both in NLRlow (<2.05) group and PLRlow group (<159.01). Changes in ER or PR expression level or status were observed in some patients. The alterations of NLR and PLR after NAC correlated with chemotherapy regimens, and elevated PLR was found. The patients with low pretreatment NLR (<1.67) or PLR (<151.27) had better responses to NAC than those with high NLR (≥1.67, 67.3 vs. 47.1%, P<0.05) or PLR (≥151.27, 64.0 vs. 45.1%, P<0.05). The patients with low pretreatment NLR (<2.05) or PLR (<159.01) had higher ER expression. Changes in ER and PR expression status or level occured following NAC. Elevated PLR was found aft-NAC. Pretreatment NLR and PLR may be important predictive indicators for NAC response in breast cancer patients.

Hormone�-receptor expression status of epithelial ovarian cancer in Ibadan, South-western Nigeria

IntroductionEpidemiological evidence strongly suggests that steroid hormones are implicated in the pathogenesis of ovarian cancer. Estrogen receptor (ER) and Progesterone receptor (PR) are prognostic indicators for a number of epithelial tumors and may play the same role in ovarian cancers. This study aims to evaluate the expression of ER and PR in epithelial ovarian cancer (EOC) in an African population and compare it with other prognostic factors such as age, International Federation of Gynaecology and Obstetrics (FIGO) stage, grade and histological subtype.MethodsNinety cases of histologically confirmed EOC were reviewed. Immunohistochemistry was used to assess their ER and PR expression status and was then compared with other demographic variables using statistical methods, with level of significance set at p < 0.05.Results30.2% and 8.3% of serous and mucinous carcinomas respectively were ER positive while 41.2% and 22.5% of both tumour types were PR positive. One of the two endometrioid carcinomas showed PR expression but neither were positive for ER. The only case of Brenner tumour in the series was ER positive but negative for PR. There was a significant association between ER and the histological subtypes (p = 0.042) while no significant association was found between PR expression and histological subtypes (p = 0.650). No significant association was found between hormone receptor status, age and stage of the EOC.ConclusionThe study showed a lower ER expression in serous carcinoma compared to large cohorts from developed countries. Future translational studies could be used to determine response of EOC to endocrine therapy.

Progesterone receptor expression is associated with longer overall survival within high-grade histotypes of endometrial carcinoma: A Canadian high risk endometrial cancer consortium (CHREC) study

ObjectiveTo assess the association of hormone receptor expression with outcome in high-grade endometrial carcinomas. MethodsThis study included three sites participating in the Canadian High Risk Endometrial Cancer (CHREC) consortium. Sections from tissue microarrays containing cases with a diagnosis of endometrioid grade 3 (EC3) and endometrial serous carcinoma (ESC) were assessed for estrogen (ER) and progesterone receptor (PR) expression by immunohistochemistry. Expression was considered present if >1% of tumor cell nuclei were labeled. Associations with overall survival were assessed. ResultsER expression was present in 168/216 (78%) of EC3 and 124/192 (65%) of ESC. PR expression was present in 148/212 (70%) of EC3 and 83/196 (42%) of ESC.PR expression was significantly associated with favorable overall survival in EC3 and ESC (log rank, p=0.018 and p=0.0024) but ER expression was not. PR expression was significantly associated with favorable overall survival in EC3 independent of age, stage, center and lymph-vascular invasion (hazard ratio=0.457, 95% CI 0.257–0.811, p=0.0075) as well as in stage I and II ESC (hazard ratio=0.266, 95% CI 0.094–0.750, p=0.0123). ConclusionOur data provide support for the assessment of the PR expression status in EC3 and ESC. Future work will be required to determine how PR expression may be incorporated into management of patients with EC3 and ESC.

Abstract P5-08-23: Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive breast cancer

Abstract Background Immunohistochemistry markers are recognized as a predictive prognostic factor for women with breast cancer. Ki-67 and progesterone receptor (PgR) expression are reported to be independently associated with breast cancer prognosis. Some studies report high Ki-67 expression as a negative predictive marker. Whereas other studies report tendency of similar survival between high and low Ki67 cancers when PgR expression is high. In this study, we examined the prognostic significance of Ki-67 expression under PgR expression status. Methods The records of 2,366 patients were retrospectively reviewed. The patients underwent surgery for primary breast cancer from July 2009 to December 2012 at a single institution. We studied the prognostic significance of Ki-67 expression under PgR expression. We used 20% and 10% as the cut-off value for PgR and Ki-67, respectively. The end point was recurrence-free survival (RFS) evaluated by use of Kaplan-Meier analysis. Result Of the 2,366 analyzed patients, the median follow-up time was 43 months. During follow-up, 44 patients had recurrence, loco-regional recurrence developed in 23 patients and distant recurrence developed in 21 patients. In patients with low PgR expression, high Ki-67 expression group showed significantly worse prognosis compared to low Ki-67 expression group (p=0.005). On the other hand, no significant difference was shown between low and high Ki-67 expression group when PgR expression was high (p=0.637). Also multivariate analysis demonstrated that high Ki-67 expression was an independent prognostic factor only when PgR expression was low. (95% confidence interval [CI], 1.35-10.48; p=0.011) Conclusion This is the largest reported study that prognostic significance of Ki-67 expression is defined by PgR expression. Our study presents that high Ki-67 expression is inversely correlated with recurrence risk in early breast cancer patients only under low PgR expression. At high PgR expression, Ki-67 expression has no influence on breast cancer prognosis. Therefore, attention should be paid to correlation between PgR and Ki-67 expression. Citation Format: Han JH, Kang YJ, Han W, Lee H-B, Kim Y, Yoo T-K, Moon H-G, Noh D-Y. Ki-67 expression is not a valuable predictive prognostic factor when progesterone receptor expression is high in estrogen receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-08-23.

Progesterone receptor expression status in a patient who received multiple courses of conservative progestin therapy: a case report of laparoscopic hysterectomy for endometrial carcinoma

Progesterone receptor expression status in a patient who received multiple courses of conservative progestin therapy: a case report of laparoscopic hysterectomy for endometrial carcinoma

Association of PKCζ Expression with Clinicopathological Characteristics of Breast Cancer

The protein kinase C (PKC) family has been functionally linked to cancer. It has been suggested that atypical PKCs contribute to cell proliferation and cancer progression. With respect to breast cancer, PKCζ has been found to play a key role in intracellular transduction of mitogenic and apoptotic signals using mammary cell lines. However, little is known about its function in vivo. Here we examined the correlation between PKCζ protein levels and important clinicopathologic factors in breast cancer using patient samples. To conduct the study, 30 invasive ductal carcinoma cases and their paired normal tissues were used for tissue microarray analysis (TMA) and 16 were used for western blot analysis. In addition, the correlation between PKCζ expression levels and clinicopathologic characteristics was determined in 176 cases with relevant clinical data. Finally, the correlation between PKCζ and epithelial growth factor receptor 2 (HER2) expressions was determined using three breast cancer cell lines by western blot analysis. Both TMA and western blot results showed that PKCζ protein was highly expressed in primary tumors but not in paired normal tissue. The correlation study indicated that high PKCζ levels were associated with premenopausal patients (p = 0.019) and worse prognostic factors, such as advanced clinical stage, more lymph node involvement and larger tumor size. Both disease-free survival and overall survival rates were lower in the high PKCζ group than those in the low PKCζ group. No correlation was observed between PKCζ levels and age, histological grade, or estrogen or progesterone receptor expression status. A positive correlation between PKCζ and HER2 levels was observed in both tumor samples and cell lines. Our observations link PKCζ expression with factors pointing to worse prognosis, higher HER2 levels and a lower survival rate. This suggests that PKCζ protein levels may serve as a prognostic marker of breast cancer.

Genomic Instability Within Tumor Stroma and Clinicopathological Characteristics of Sporadic Primary Invasive Breast Carcinoma

That genomic alterations occur in both the epithelium and stroma of sporadic breast cancers has been documented by several groups. However, whether these microenvironmental alterations relate to clinicopathological features is unknown. To analyze the relationship between stromal genomic alterations and presenting clinicopathological features in sporadic breast cancer. A retrospective cross-sectional analysis of DNA from the epithelium and stroma of 220 primary sporadic invasive breast carcinomas for global genomic alterations manifested by loss of heterozygosity/allelic imbalance with 386 microsatellite markers. Data were collected from October 2003 through June 2006 from samples at Brigham and Women's Hospital, Boston, Mass. Association of the loss of heterozygosity/allelic imbalance, in both the stroma and epithelium, with presenting clinicopathological features, such as tumor grade, expression status of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2, clinical stage, and regional lymph node metastasis status. Associations were assessed in regression models and tested with Fisher exact test. Bonferroni correction was applied to P values, with significance set at P<.0022. We found significant associations between loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma and tumor grade (P = .0013), on chromosomes 1, 2, 5, 18, 20, and 22 in the stroma and regional lymph node metastasis (P = .0002-.0016), and on chromosome 14 in the epithelium and progesterone-receptor expression status (P = .002). Specific markers contributing to the loss of heterozygosity/allelic imbalance on chromosome 11 in the stroma associated with tumor grade were D11S1999 (P = .00055) and D11S1986 (P = .042). The loss of heterozygosity/allelic imbalance at various markers in the stroma was significantly associated with regional lymph node metastasis: ATA42G12 (chromosome 1, P = .00095), D5S1457 (P = .00095), D5S1501 (P = .0011), D5S816 (P = .0008), D18S858 (P = .0026), D20S103 (P = .0027), D20S851 (P = .0045), D22S683 (P = .00033), and D22S1045 (P = .0013). There were more correlations between clinicopathological features and the loss of heterozygosity/allelic imbalance in the stroma than in the epithelium, suggesting that stromal genomic alterations may help account for clinical diversity. Future research is necessary to validate these results and investigate their significance for prognosis and outcome.