Glucocorticoid receptor-mediated oncogenic activity is dependent on breast cancer subtype.

Breast cancer incidence has been steadily rising and is the leading cause of cancer death in women due to its high metastatic potential. Individual breast cancer subtypes are classified by both cell type of origin and receptor expression, namely estrogen, progesterone and human epidermal growth factor receptors (ER, PR and HER2). Recently, the importance and context-dependent role of glucocorticoid receptor (GR) expression in the natural history and prognosis of breast cancer subtypes have been uncovered.

Glucocorticoid Receptor (GR) Activation Is Associated with Increased cAMP/PKA Signaling in Castration-Resistant Prostate Cancer.

In castration-resistant prostate cancer (CRPC), increased glucocorticoid receptor (GR) expression and ensuing transcriptional activity have been proposed as an oncogenic "bypass" mechanism in response to androgen receptor (AR) signaling inhibition (ARSi). Here, we report that GR transcriptional activity acquired following ARSi is associated with the upregulation of cyclic adenosine monophosphate (cAMP)-associated gene expression pathways in both model systems and metastatic prostate cancer patient samples. In the context of ARSi, the expression of GR-mediated genes encoding cAMP signaling pathway-associated proteins can be inhibited by treatment with selective GR modulators (SGRMs).

Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases.

Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC's unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces.

High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas.

Glucocorticoid receptor can be associated with poor prognosis among a variety of solid tumors in the absence of other nuclear hormone receptors. Our objective was to characterize differences in glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor expression in the sarcomatous versus carcinomatous components of ovarian and uterine carcinosarcomas. Eighteen patients diagnosed with Mullerian carcinosarcoma between May 2009 and August 2014 were included.

The Role of Psychologic Stress in Cancer Initiation: Clinical Relevance and Potential Molecular Mechanisms.

The hypothesis that the physiologic response to psychologic stress influences the initiation of cancer is highly controversial. The link between initiating stressors, the psychologic stress response, and disease is plausible, considering that the stress response is associated with defined physiologic outcomes and molecular mechanisms. In light of this, we review the clinical relevance of psychologic stress on the risk of cancer, and we propose potential molecular pathways that may link the stress response to early stages of malignant cell transformation.

Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview.

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent.

Magnetic resonance angiography reveals increased arterial blood supply and tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer.

Breast cancer is the second most commonly diagnosed malignancy among women globally. Past MRI studies have linked a high animal fat diet (HAFD) to increased mammary cancer risk in the SV40Tag mouse model of triple-negative breast cancer. Here, serial MRI examines tumor progression and measures the arterial blood volume feeding mammary glands in low fat diet (LFD) or HAFD fed mice.

Improving research for prostate cancer survivorship: A statement from the Survivorship Research in Prostate Cancer (SuRECaP) working group.

Survivorship care for patients with prostate cancer requires careful consideration of unique disease-specific factors, including the prolonged natural disease history, the potential for competing health risks, and the consequences of long-term androgen deprivation therapy. However, current prostate cancer survivorship research is unfortunately limited by the lack of a robust supportive evidence base, variability in the definitions and measurement of survivorship outcomes, and a heavy reliance on expert opinion. As a result, the conduct of quality prostate cancer survivorship research is of increasing importance for patients, medical providers, and other key stakeholders.

Glucocorticoid receptor modulation decreases ER-positive breast cancer cell proliferation and suppresses wild-type and mutant ER chromatin association.

Background: Non-ER nuclear receptor activity can alter estrogen receptor (ER) chromatin association and resultant ER-mediated transcription. Consistent with GR modulation of ER activity, high tumor glucocorticoid receptor (GR) expression correlates with improved relapse-free survival in ER+ breast cancer (BC) patients.

Methods: In vitro cell proliferation assays were used to assess ER-mediated BC cell proliferation following GR modulation.

Radiogenomics of breast cancer using dynamic contrast enhanced MRI and gene expression profiling.

Background: Imaging techniques can provide information about the tumor non-invasively and have been shown to provide information about the underlying genetic makeup. Correlating image-based phenotypes (radiomics) with genomic analyses is an emerging area of research commonly referred to as "radiogenomics" or "imaging-genomics". The purpose of this study was to assess the potential for using an automated, quantitative radiomics platform on magnetic resonance (MR) breast imaging for inferring underlying activity of clinically relevant gene pathways derived from RNA sequencing of invasive breast cancers prior to therapy.

Magnetic Resonance Angiography Shows Increased Arterial Blood Supply Associated with Murine Mammary Cancer.

Breast cancer is a major cause of morbidity and mortality in Western women. Tumor neoangiogenesis, the formation of new blood vessels from pre-existing ones, may be used as a prognostic marker for cancer progression. Clinical practice uses dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to detect cancers based on increased blood flow and capillary permeability.

Glucocorticoid receptor expression is associated with inferior overall survival independent of BRCA mutation status in ovarian cancer.

Objective: High glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.

Psychosocial Stress Exposure Disrupts Mammary Gland Development.

Exposure to psychosocial stressors and ensuing stress physiology have been associated with spontaneous invasive mammary tumors in the Sprague-Dawley rat model of human breast cancer. Mammary gland (MG) development is a time when physiologic and environmental exposures influence breast cancer risk. However, the effect of psychosocial stress exposure on MG development remains unknown.

Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer.

Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297.

Racial disparities in omission of oncotype DX but no racial disparities in chemotherapy receipt following completed oncotype DX test results.

Purpose: To examine racial/ethnic disparities in Oncotype DX (ODX) testing among patients with node-negative, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers and possible racial/ethnic disparities in chemotherapy receipt following ODX testing within Recurrence Score (RS) category (Not Done, Low, Intermediate, High), as well as chemotherapy receipt time trends within RS categories.

Methods: A retrospective cohort list of 125,288 women who were potentially indicated for ODX testing from 2010 to 2014 was obtained using the National Cancer Database. We fit multivariate logistic regression predicting chemotherapy receipt, adjusting for clinical factors, patient demographic factors, and hospital-level factors, separately by RS category, and calculated odds ratios (OR) and 95% confidence intervals (CI), as well as time trends.

Metabolism of megestrol acetate in vitro and the role of oxidative metabolites.

1. There is limited knowledge regarding the metabolism of megestrol acetate (MA), as it was approved by FDA in 1971, prior to the availability of modern tools for identifying specific drug-metabolizing enzymes. We determined the cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs) that metabolize MA, identified oxidative metabolites and determined pharmacologic activity at the progesterone, androgen and glucocorticoid receptors (PR, AR and GR, respectively).

Expression of glucocorticoid receptor is associated with aggressive primary endometrial cancer and increases from primary to metastatic lesions.

Background: Glucocorticoid receptor (GR) has emerged as an important steroid nuclear receptor in hormone dependent cancers, however few data are available regarding a potential role of GR in endometrial cancer. The aim of this study was to investigate expression of GR in primary and metastatic endometrial cancer lesions, and to assess the relationship between GR expression and clinical and histopathological variables and survival.

Methods: Expression of GR was investigated by IHC in 724 primary tumors and 289 metastatic lesions (from 135 patients), and correlations with clinical and histopathological data and survival were explored.

MRI reveals increased tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer.

High animal fat consumption is associated with an increase in triple-negative breast cancer (TNBC) risk. Based on previous MRI studies demonstrating the feasibility of detecting very early non-palpable mammary cancers in simian virus 40 large T antigen (SV40TAg) mice, we examined the effect of dietary fat fed from weaning to young adulthood in this model of TNBC. Virgin female C3(1)SV40TAg mice (n = 16) were weaned at 3-4 weeks of age and then fed either a low fat diet (LFD) (n = 8, 3.

High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer.

Objective: To investigate the association of tumor glucocorticoid receptor (GR) expression and patient outcome in ovarian cancer.

Methods: GR expression was evaluated by immunohistochemistry using tissue microarrays of specimens from 481 patients with ovarian cancer and 4 patients with benign conditions. Low GR expression was defined as an intensity of 0 or 1+ and high GR as 2+ or 3+ in >1% of tumor cells.