Erratum to: Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue.

Erratum to: Breast Cancer Res Treat (2013),142:283­296,DOI 10.1007/s10549-013-2722-8. In the original publication of the article, the blot corresponding to the total P38 protein content for the conditions siCtl and siBRCA1 in Fig. 7a was incorrectly laid out. The corrected Fig. 7a is given in this erratum.The

Clusterin expression in gastrointestinal neuroendocrine tumours is highly correlated with location and is helpful in determining the origin of liver metastases.

AIMS: Clusterin (CLU) is a sulphated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. We have previously demonstrated that CLU is highly expressed in pancreatic neuroendocrine tumours (NETs). The aims of this study were: to investigate CLU expression in gastrointestinal NETs; the potential correlation between this expression and different clinicopathological parameters; and its usefulness in the differential diagnosis of liver metastases. METHODS AND RESULTS: Immunohistochemistry using an anti-CLU antibody was performed on paraffin sections from 108 primary NETs [G3 (13 cases), G2 (18 cases), and G1 (77 cases), according to the 2010 WHO classification] and 60 metastases. Cytoplasmic positivity was scored qualitatively and quantitatively. The pattern of staining was also assessed. Two-step statistical analyses (univariate and multivariate logistic regression) were performed. More than 90% of small-intestine NETs were completely negative. The probability of obtaining a positive CLU score was higher for the appendix, the stomach, the duodenum and the rectum than for the small intestine and colon. All G3 NETs and most G2 NETs were negative as compared with G1. CLU expression in the metastatic foci was identical to that of the primary tumour. CONCLUSIONS: Clusterin expression in gastrointestinal NETs is highly correlated with location and probably also with grading, in both the primary tumour and metastases. Underexpression of CLU in small-intestine NETs is helpful for identifying the origin of liver metastases: a strong CLU score in a liver biopsy makes the small intestine highly unlikely as a primary site.

Loss of glucocorticoid receptor activation is a hallmark of BRCA1-mutated breast tissue.

Glucocorticoids (GCs) regulate cell homeostasis and can affect carcinogenesis. An inherited germline mutation in the BRCA1 gene, a tumor suppressor gene, confers a predisposition to breast and ovarian cancers. BRCA1 participates in the maintenance of genome stability through DNA repair, in cellular homeostasis through gene transcription, and in signaling regulation. The interaction between BRCA1 and the glucocorticoid receptor (GR) signaling pathway was studied in normal breast tissues and triple-negative breast cancers from BRCA1 mutation carriers. A loss of the active Ser211 phosphorylated form of GR was found in the mutant as compared to the non-mutant. In in vitro studies, the BRCA1 status in breast cancer cell lines regulates GC-dependent proliferation/apoptosis and impacts GC-dependent gene expression. The lack of BRCA1 inhibited dexamethasone actions on its target genes' expression and the opposite effect was seen with BRCA1 overexpression. BRCA1 overexpression enhances MAPK p38 phosphorylation, resulting in an amplification of GR phosphorylation on Ser 211 and GR basal expression. Our results indicate that BRCA1 is essential to develop an efficient GC signalization. GR P-Ser211 levels may constitute an important diagnostic factor for screening BRCA1 loss of expression in tumors from BRCA1 mutation carriers as well as in sporadic BRCAness tumors. This marker may help to optimize therapeutic strategies.

Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells.

The purpose of this article is to determine the tumorigenic potential of estradiol treatment (E2) when combined with either progesterone (P4) or medroxyprogesterone acetate (MPA) in normal luminal human breast cells (HBE) and in human breast cancer cells (T47-D, MCF-7). Proliferation profiles were evaluated, along with the gene transactivation activity between the progesterone and glucocorticoid receptors (PR, GR) in HBE, T47-D, and MCF-7 cells treated by E2 + P4 or E2 + MPA. High throughput transcriptome analysis was performed on RNA from HBE cells treated by E2, E2 + MPA and E2 + P4. GR content was analyzed in normal breast cells as well. In HBE cells, E2 + P4 treatment was antiproliferative and promoted cellular differentiation. In contrast, E2 + MPA displayed mitogenic, antiapoptotic effects in HBE cells and did not influence cellular differentiation. The effect of P4 and MPA on cell proliferation was, however, variable in breast cancer cells. In cells containing GR or/and PR, MPA decreased proliferation whereas P4 antiproliferative effect needed the presence of PR. In HBE cells, the regulation of genes by E2 + P4, and E2 + MPA was significantly different, particularly in cell proliferation and cell death gene families. Further analysis revealed a modulation of the glucocorticoid receptor gene expression pathway by E2 + MPA. Predominant MPA glucocorticoid activity in normal and breast cancer cells was demonstrated using a glucocorticoid antagonist and the down-regulation of the GR by RNA interference. In normal luminal breast cells and in breast cancer cells, P4 and MPA combined with E2 treatment have opposing mitogenic effects due to GR. The consequences of MPA glucocorticoid potencies as well as the importance of GR in breast tissue merit a reappraisal.

Ulipristal acetate does not impact human normal breast tissue.

BACKGROUND: Antiprogestins are of growing interest for the development of new treatments in the gynecological field. Ulipristal acetate (UPA) is a progesterone receptor (PR) modulator considered for long-term administration in contraception and is currently being registered for the treatment of uterine fibroids. In light of the influences of hormonal dysfunction in breast pathologies, the secondary consequences of chronic UPA therapy need to be established. The aim of this study was to determine UPA actions mediated by PR and glucocorticoid receptor (GR) in normal and transformed breast. METHODS: UPA, progesterone (P) and dexamethasone (DEX) effects were observed on PR and GR responsive genes and on proliferation and apoptosis of normal human breast epithelial (HBE) and breast cancer cells. Human normal breast tissue samples were xenografted in athymic mice and treated with estradiol (E2), or E2 + P, or E2 + P + UPA. RESULTS: Analysis of PR and GR reporter gene transactivation and their respective endogenous target genes indicated that UPA exerted anti-progestational and anti-glucocorticoid activity in both types of cells with a more pronounced effect in cancer cells. When combined with P or DEX, UPA limits the proliferation of HBE cells but increases growth in breast cancer cell lines. UPA administration had no impact on the mitotic index on xenografted human breast tissue exposed to gonadal hormones at similar concentrations to those present in normal women. CONCLUSIONS: Although further clinical trials are required to confirm that the results from our experimental models can be extrapolated to women treated with UPA, they suggest that such treatment would not be deleterious to normal breast tissue at least for a cycle (28 days) of continuous administration.

Glucocorticoid receptor and breast cancer.

Stress enhances glucocorticoid (GC) synthesis, which alters inflammation and immune responses, as well as cellular proliferation and apoptosis in a number of tissues. Increasingly, stress has been associated with cancer progression, and in particular in breast cancer. Consequently, an operational glucocorticoid receptor system in breast tissue influences breast cancer development. In this review, we summarize the data on the GC/GR system in normal and tumoral breast tissue. We also review the molecular mechanisms by which GCs control apoptosis and proliferation in breast cancer models and how GCs alter the chemotherapy of breast cancer treatment when used in combination. Finally, we discuss the participation of GR in breast tumorigenesis under hormone replacement therapy.

Lumboaortic and iliac lymphadenectomy for lymph node recurrence of colorectal cancer: prognostic value of the MSI phenotype.

BACKGROUND: Some patients have isolated lumboaortic and/or iliac lymph node recurrences (ILNR) of colorectal cancer. Current guidelines recommend the use of chemotherapy. The aim of our study was to assess the carcinological results of lymphadenectomy for ILNR and to identify prognostic factors that may be used to select patients for this aggressive surgical approach. METHODS: Medical notes, pathological findings, and surgical procedure of patients who underwent lymphadenectomy for ILNR of colorectal cancer between 1998 and 2005 were reviewed. RESULTS: Ten patients (four women) underwent lymphadenectomy for ILNR. Lymphadenectomy was performed after a mean of 37 +/- 16.6 months after colon or rectal resection. Two patients developed a postoperative complication. Mean number of lymph nodes removed was 5.7 +/- 3.3. After a median follow-up of 30.7 months, four patients were alive, including two patients without recurrence at 95 and 96 months after colectomy and two with local and distant recurrences at 114 and 70 months. Among the three patients with microsatellite-unstable (MSI) tumors, two were free of disease at 61 and 81 months, respectively, and one died of recurrent disease 20 months after lymphadenectomy. CONCLUSION: Lymphadenectomy for ILNR of colorectal cancer is a feasible therapeutic option for selected patients. These preliminary results suggest that resection should be proposed for MSI patients because cure is possible, but to be confirmed, the findings require larger studies.

Adrenalectomy for clinically isolated metastasis from colorectal carcinoma: report of eight cases.

PURPOSE: Metastasis to the adrenal glands is a relatively frequent finding at autopsy. Adrenal metastasis of colorectal carcinoma is rare (14 percent). Isolated adrenal metastasis is even rarer, and presents a therapeutic dilemma. METHODS: Between 1997 and 2006, eight patients (5 men; mean age, 62 years) underwent adrenalectomy for metastasis of colorectal carcinoma. The tumors were Stage D in four cases, Stage B in two cases, and Stage C in the remaining two. Adjuvant chemotherapy was instituted. RESULTS: All patients were asymptomatic, and adrenal metastasis was suspected from an elevated serum level of carcinoembryogenic antigen or discovered by computed tomography. Adrenal metastases were metachronous in seven patients, with median disease-free interval of 3.75 years. At the time of follow-up, one patient remained alive and free of disease 12 months after adrenalectomy, one patient was lost to follow-up after 22 months, and 6 patients have died from malignancy. The mean survival for the patients who died was 32 months. CONCLUSIONS: The rarity of isolated adrenal metastasis of colorectal carcinoma makes a randomized, prospective trial comparing surgery vs. nonsurgical management highly unlikely. Our results provide further support for surgical resection of solitary adrenal metastasis, which may translate into survival benefit.

Multiple stomas for recurrent life-threatening gastrointestinal bleeding: report of a case.

Acute lower gastrointestinal hemorrhage is an uncommon and severe symptom. The overall mortality rate ranges from 5 to 12 percent and can approach 40 percent for persistent or recurring bleedings. We report a case of a patient with severe recurrent lower bleeding in whom, despite several repeated explorations and a blind subtotal colectomy, no lesion could be found. Multiple (n = 4) leveled stomas of the small bowel with succus entericus reinfusion were required to localize and treat the cause of the bleeding. This case report is followed by a review of the literature of the management of lower gastrointestinal bleeding.

Genomic profile of colon cancer metastases.

BACKGROUND: In colon cancer, the occurrence of metastases is associated with microsatellite stability. As metastatic cells derive from a clonal expansion of primary tumor cells, specific genomic alterations are expected in addition to the common genomic profile. PATIENTS AND METHODS: Genome-wide allelotyping was performed on 75 liver metastases samples from sporadic colon cancer. RESULTS: No microsatellite instability was observed. Allelic loss on 5q in metastases was significantly different from that of non metastatic primary tumors (16/58 vs. 43/75, p=0.0008). Four additional chromosomes, 4, 7, 8 and 19, were more frequently lost in liver metastases, but statistical significance was reached only for 19q (14/63 versus 2/68 in primary tumors; p=0.033 after Dunn-Sidak adjustment). CONCLUSION: This study confirms that liver metastasis is rather restricted to patients with microsatellite stable colon cancer and these retain the 5q arm with high frequency. In addition, it suggests that loss of 19q may be critical for one of the steps involved in the development of liver metastases.

Clusterin expression in medullary thyroid carcinoma is inversely correlated with the presence of lymph node metastases.

Clusterin (CLU) is a sulfated glycoprotein implicated in many physiological and pathological processes, including tumorigenesis. Several studies have reported the overexpression of CLU in human neoplasm, examined by immunohistochemistry. However, there are no extensive data on its role in the thyroid. Here we investigate CLU expression in thyroid tumors, and the potential correlation between this expression and clinicopathological parameters. Immunohistochemistry with anti-CLU was performed on paraffin sections from 39 thyroid tumors. Only medullary thyroid carcinomas (MTCs) were positive (n = 5). To confirm these results, 130 further cases (including 4 C-cell hyperplasia), their matched lymph node metastases (46 cases), and lymph node recurrences (10 cases) were analyzed. All MTCs were subdivided according to World Health Organization classification. Cytoplasmic positivity was scored qualitatively (weak, moderate, strong) and quantitatively on a 5-tier scale from 0, 1+ (<10% of cells positive) to 5+ (>75%). Statistical analysis was performed. CLU was expressed in normal C cells, C-cell hyperplasia, all MTCs, their lymph node metastases, and recurrences. There was a strong association between CLU score and the cellular type (P < .004). CLU score was inversely correlated with the presence of lymph node metastases (P < .0001). There were no differences between primary and metastatic or recurrent tumors. CLU expression is related to the cellular type and inversely correlated with the presence of lymph node metastases, which could represent a new positive prognostic factor.

MRI of rectal disorders.

OBJECTIVE: The objective of this pictorial essay is to provide a review of the diseases involving the rectal wall with an emphasis on the key clinical and radiologic differentiating features. CONCLUSION: A wide spectrum of disease processes can involve the rectum in adults. MRI is the technique of choice in the definitive diagnosis of these disease conditions, mainly because of its superior tissue contrast differentiation.