Tumor Progesterone Receptor Expression Research Articles

Overexpression of long non-coding RNA MCM3AP-AS1 in breast cancer tissues compared to adjacent non-tumour tissues

ABSTRACT Background Altered expression of several long non-coding RNAs (lncRNAs) has been described in numerous malignancies, including breast cancer, and some may have a role in carcinogenesis. We hypothesised differences in the expression of lncRNA MCM3AP-AS1 in breast cancer tissues compared to nearby healthy tissues and potential links with clinical features. Methods We tested our hypothesis in 102 pairs of breast cancer tumours and adjacent non-tumour tissues from female patients. After RNA extraction, cDNA synthesis was performed for all specimens. The differential gene expression was assessed using Quantitative Real-Time PCR Technique. Results There was a significant overexpression of the lncRNAs in tumour tissues as compared with their adjacent non-tumour tissues (P < 0.001). Expression was significantly linked with the tumour oestrogen receptor expression (P = 0.023) and tumour progesterone receptor expression (P < 0.001). ROC analysis showed an AUC of 0.67 (95% CI 0.60–0.75) (P < 0.001) with sensitivity and specificity of 58% and 76%, respectively Conclusion The lncRNA MCM3AP-AS1 may be a novel breast cancer lncRNA with high expression levels in breast cancer patients’ tissue. Further investigations are needed to confirm its uses as a potential molecular marker and therapeutic target.

Abstract B44: Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas

Abstract Purpose: Progesterone receptor (PR) is expressed strongly in a subset of neuroendocrine cells in the pancreas. Tamoxifen has long been used in adjuvant endocrine therapy of steroid hormone receptor–positive breast cancer, and currently clinical trials are assessing its use in pancreatic neuroendocrine tumors (NET) that show variable PR expression. Prior studies have reported receptor status as “positive” or “negative,” using 1% or 10% positive nuclei as a cutoff. In this study, we assessed PR immunohistochemical expression in a cohort of NET and other pancreatic nonexocrine carcinomas. Theoretically, tumors with highest PR expression are more likely to respond to adjuvant tamoxifen. Experimental Design: Immunohistochemical staining for PR was performed on tissue microarrays of 54 well-differentiated neuroendocrine tumors of the pancreas and 8 poorly differentiated carcinomas of the pancreas, including 4 acinar cell carcinomas, 2 neuroendocrine carcinomas, and 2 small-cell neuroendocrine carcinomas. A minimum of 4 separate 2-mm tumor cores were sampled on each case. Results: PR expression in non-neoplastic pancreatic islets was used for positive control. PR staining was evaluated using a semiquantitative H-score method. Positive PR staining (defined as greater than 1%) was identified in 61% (33 of 54 cases) of well-differentiated NET (mean H-score 100) and 0% (0 of 8 cases) of poorly differentiated carcinomas of the pancreas. Of the 33 PR positive cases of well-differentiated NET, 3 cases had less than 10% nuclear staining (mean H-score 7), 8 cases had 10% to less than 50% nuclear staining (mean H-score 44), and 22 cases had 50% or greater nuclear staining (mean H-score 229). Conclusions: Based on these findings, we suggest analysis of NET tumor PR expression should include a quantitative or semiquantitative score rather than dichotomized immunohistochemical evaluation of hormone receptors, particularly in the evaluation of patients’ response to clinical trials with tamoxifen. High-grade endocrine and acinar carcinomas showed no PR expression and are less likely to derive benefit from adjuvant endocrine therapy. Citation Format: Sonya Purushothaman, Simona De Michele, Dorothy Low, Helen E. Remotti. Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B44.

Transcript expression and genetic variability analysis of caspases in breast carcinomas suggests CASP9 as the most interesting target.

Apoptosis plays a critical role in cancer cell survival and tumor development. We provide a hypothesis-generating screen for further research by exploring the expression profile and genetic variability of caspases (2, 3, 7, 8, 9, and 10) in breast carcinoma patients. This study addressed isoform-specific caspase transcript expression and genetic variability in regulatory sequences of caspases 2 and 9. Gene expression profiling was performed by quantitative real-time PCR in tumor and paired non-malignant tissues of two independent groups of patients. Genetic variability was determined by high resolution melting, allelic discrimination, and sequencing analysis in tumor and peripheral blood lymphocyte DNA of the patients. CASP3 A+B and S isoforms were over-expressed in tumors of both patient groups. The CASP9 transcript was down-regulated in tumors of both groups of patients and significantly associated with expression of hormonal receptors and with the presence of rs4645978-rs2020903-rs4646034 haplotype in the CASP9 gene. Patients with a low intratumoral CASP9A/B isoform expression ratio (predicted to shift equilibrium towards anti-apoptotic isoform) subsequently treated with adjuvant chemotherapy had a significantly shorter disease-free survival than those with the high ratio (p=0.04). Inheritance of CC genotype of rs2020903 in CASP9 was associated with progesterone receptor expression in tumors (p=0.003). Genetic variability in CASP9 and expression of its splicing variants present targets for further study.

Dietary fiber intake and risk of hormonal receptor–defined breast cancer in the European Prospective Investigation into Cancer and Nutrition study

Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors. We investigated the relation between total dietary fiber and its main food sources (vegetables, fruit, cereals, and legumes) and BC risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 11,576 invasive BC cases in 334,849 EPIC women mostly aged 35-70 y at baseline were identified over a median follow-up of 11.5 y. Dietary fiber was estimated from country-specific dietary questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk with energy adjustment by using the residual method. Subgroup analyses were performed by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) expression in tumors. BC risk was inversely associated with intakes of total dietary fiber [hazard ratio comparing fifth quintile to first quintile (HR(Q5-Q1)): 0.95; 95% CI: 0.89, 1.01; P-trend = 0.03] and fiber from vegetables (0.90; 0.84, 0.96; P-trend < 0.01) but not with fiber from fruit, cereals, or legumes. Overall, associations were homogeneous by menopausal status and ER and PR expression in tumors. For vegetable fiber, stronger associations were observed for estrogen receptor-negative and progesterone receptor-negative (HR(Q5-Q1):0.74; 95% CI: 0.59, 0.93; P-trend = 0.01) than for estrogen receptor-positive and progesterone receptor-positive tumors (0.92: 0.81, 1.03; P-trend = 0.05), with P-heterogeneity = 0.09. Diets rich in dietary fiber and, particularly, fiber from vegetables may be associated with a small reduction in risk of BC, independently of menopausal status.

Obesity and Overfeeding Affecting Both Tumor and Systemic Metabolism Activates the Progesterone Receptor to Contribute to Postmenopausal Breast Cancer

Obese postmenopausal women have increased risk of breast cancers with poorer clinical outcomes than their lean counterparts. However, the mechanisms underlying these associations are poorly understood. Rodent model studies have recently identified a period of vulnerability for mammary cancer promotion, which emerges during weight gain after the loss of ovarian function (surgical ovariectomy; OVX). Thus, a period of transient weight gain may provide a life cycle-specific opportunity to prevent or treat postmenopausal breast cancer. We hypothesized that a combination of impaired metabolic regulation in obese animals prior to OVX plus an OVX-induced positive energy imbalance might cooperate to drive tumor growth and progression. To determine if lean and obese rodents differ in their metabolic response to OVX-induced weight gain, and whether this difference affects later mammary tumor metabolism, we performed a nutrient tracer study during the menopausal window of vulnerability. Lean animals preferentially deposited excess nutrients to mammary and peripheral tissues rather than to the adjacent tumors. Conversely, obese animals deposited excess nutrients into the tumors themselves. Notably, tumors from obese animals also displayed increased expression of the progesterone receptor (PR). Elevated PR expression positively correlated with tumor expression of glycolytic and lipogenic enzymes, glucose uptake, and proliferation markers. Treatment with the antidiabetic drug metformin during ovariectomy-induced weight gain caused tumor regression and downregulation of PR expression in tumors. Clinically, expression array analysis of breast tumors from postmenopausal women revealed that PR expression correlated with a similar pattern of metabolic upregulation, supporting the notion that PR+ tumors have enhanced metabolic capacity after menopause. Our findings have potential explanative power in understanding why obese, postmenopausal women display an increased risk of breast cancer.