Background

The study aimed to examine the association between health-related quality of life (HRQOL) assessed with overall survival (OS) and recurrence after diagnosis of colorectal cancer (CRC).

Methods

Overall 160 patients with advanced stage CRC were recruited in an observational study and completed the generic and condition-specific HRQOL questionnaires at the colorectal specialist outpatient clinic in Hong Kong, between 10/2009 and 07/2010. Socio-demographic and clinical characteristics including duration since diagnosis, primary tumor location and treatment modality, were collected to serve as predictor variables in regression models. All-cause death or CRC recurrence was the event of interest. Association between HRQOL with OS was assessed using Cox regression. Association between HRQOL and CRC recurrence was further modeled by competing-risks regression adjusted for the competing-risks of death from any cause.

Results

After a median follow-up of 23 months, there were 22 (16.1%) incidents of CRC recurrence and 15 (9.4%) deaths. Decreased physical functioning (hazard ratios, HR = 0.917, 95% CI:0.889-0.981) and general health of domains in SF-12 (HR = 0.846, 95% CI:0.746-0.958) or SF-6D scores (HR = 0.010, 95% CI:0.000-0.573) were associated with an increased risk of death, with adjustment of patients’ characteristics. Increased vitality (HR = 1.151, 95% CI:1.027-1.289) and mental health (HR = 1.128, 95% CI:1.005-1.265) were associated with an increased likelihood of death. In models adjusted for competing-risk of death, those with worse HRQOL was not associated with increased risk of CRC recurrence.

Conclusions

Although self-reported HRQOL was not a significant prognostic factor for CRC recurrence, the HRQOL provided independent prognostic value about mortality in patients with advanced stage of CRC.

Background

RNA binding proteins (RBPs) play a fundamental role in posttranscriptional control of gene expression. Different RBPs have oncogenic or tumor-suppressive functions on human cancers. RNPC1 belongs to the RNA recognition motif (RRM) family of RBPs, which could regulate expression of diverse targets by mRNA stability in human cancer cells. Several studies reported that RNPC1 played an important role in cancer, mostly acting as an oncogene or up-regulating in tumors. However, its role in human breast cancer remains unclear.

Methods

In the present study, we investigated the functional and mechanistic roles of RNPC1 in attenuating invasive signal including reverse epithelial-mesenchymal transition (EMT) to inhibit breast cancer cells aggressiveness in vitro. Moreover, RNPC1 suppress tumorigenicity in vivo. Further, we studied the expression of RNPC1 in breast cancer tissue and adjacent normal breast tissue by quantitative RT-PCR (qRT-PCR) and Western blot.

Results

We observed that RNPC1 expression was silenced in breast cancer cell lines compared to breast epithelial cells. More important, RNPC1 was frequently silenced in breast cancer tissue compared to adjacent normal breast tissue. Low RNPC1 mRNA expression was associated with higher clinical stages and mutp53, while low level of RNPC1 protein was associated with higher lymph node metastasis, mutp53 and lower progesterone receptor (PR). Functional assays showed ectopic expression of RNPC1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing cell cycle arrest, and further suppress tumor cell migration and invasion partly through repressing mutant p53 (mutp53) induced EMT.

Conclusions

Overall, our findings indicated that RNPC1 had a potential function to play a tumor-suppressor role which may be a potential marker in the therapeutic and prognostic of breast cancer.

Background

Mechanisms governing the metastasis of endometrial cancer (EC) are poorly defined. Recent data support a role for Enhancer-of-split and hairy-related protein 1 (SHARP1), a basic helix-loop-helix transcription repressor, in regulating invasiveness and angiogenesis of several human cancers. However, the role of SHARP1 in metastasis of EC remains unclear.

Methods

Human EC cell lines (Ishikawa and HEC-1B) were used. SHARP1 was upregulated by lentivirus transduction, while intracellular domain of NOTCH1 (ICN) were upregulated by transient transfection with plasmids. Effects of SHARP1 on cell migration and invasion were evaluated by wound healing assay and transwell invasion assay. Experimental metastasis assay were performed in nude mice. Effects of SHAPR1 on protein levels of target genes were detected by western blotting. Furthermore, the association between SHARP1 and the NOTCH1/EMT pathway was further verified in EC tissue specimens by immunohistochemical analysis.

Results

Overexpression of SHARP1 in EC cells inhibited cell migration, invasion, and metastasis. Exogenous SHARP1 overexpression affected the proteins levels of genes involved in EMT process and NOTCH1 signaling pathway. Upregulation of ICN in SHARP1-overexpressing Ishikawa cells induced cell migration and an EMT phenotype. Additionally, immunohistochemical analysis demonstrated that SHARP1 protein levels were lower in metastatic EC than in primary tumors, and statistical analysis revealed correlations between levels of SHARP1 and markers of EMT and NOTCH1 signaling pathway in human EC tissue specimen.

Conclusions

This work supports a role for SHARP1 in suppressing EMT and metastasis in EC by attenuating NOTCH1 signaling. Therefore, SHARP1 may be a novel marker for lymphatic metastasis in EC patients.

Background

An early age at Breast Cancer (BC) onset may be a hallmark of inherited predisposition, but BRCA1/2 mutations are only found in a minority of younger BC patients. Among the others, a fraction may carry mutations in rarer BC genes, such as TP53, STK11, CDH1 and PTEN. As the identification of women harboring such mutations allows for targeted risk-management, the knowledge of associated manifestations and an accurate clinical and family history evaluation are warranted.

Case presentation

We describe the case of a woman who developed an infiltrating ductal carcinoma of the right breast at the age of 32, a contralateral BC at age 36 and another BC of the right breast at 40. When she was 39 years-old, during a dermatological examination, mucocutaneous features suggestive of Cowden Syndrome, a disorder associated to germ-line PTEN mutations, were noticed. PTEN genetic testing revealed the novel c.71A > T (p.Asp24Val) mutation, whose deleterious effect, suggested by conservation data and in silico tools, was definitely demonstrated by the incapacity of mutant PTEN to inhibit Akt phosphorylation when used to complement PTEN-null cells. In BC tissue, despite the absence of LOH or somatic mutations of PTEN, Akt phosphorylation was markedly increased in comparison to normal tissue, thus implying additional somatic events into the deregulation of the PI3K/Akt/mTOR pathway and, presumably, into carcinogenesis. Hence, known oncogenic mutations in PIK3CA (exons 10 and 21) and AKT1 (exon 2) were screened in tumor DNA with negative results, which suggests that the responsible somatic event(s) is a different, uncommon one.

Conclusion

This case stresses the importance of clinical/genetic assessment of early-onset BC patients in order to identify mutation carriers, who are at high risk of new events, so requiring tailored management. Moreover, it revealed a novel PTEN mutation with pathogenic effect, pointing out, however, the need for further efforts to elucidate the molecular steps of PTEN-associated carcinogenesis.

Background

In contrast with breast cancers (BCs) in other parts of the world, most previous studies reported that the majority of BCs in sub-Saharan Africa are estrogen-receptor (ER) negative. However, a recent study using the US SEER database showed that the proportion of ER-negative BC is comparable between US-born blacks and West-African born blacks but substantially lower in East African-born blacks, with over 74% of patients Ethiopians or Eritreans. In this paper, we provide the first report on the proportion of ER-negative BC in Ethiopia, and the relation to progesterone-receptor (PgR) status.

Methods

We analysed 352 female patients with ER results available out of 1208 consecutive female BC patients treated at Addis Ababa-University Hospital, Ethiopia, from June 2005 through December 2010. The influences of age, stage, and histology on the probability of ER-negative tumours were assessed by a log-linear regression model.

Results

Of the 352 patients, only 35% were ER-negative. The proportion of ER-negative tumours decreased with advancing age at diagnosis and was not affected by histology or stage. For age, the proportion decreased by 6% for each additional 5 years (stage-adjusted prevalence ratio PR = 0.94, 95% CI: 0.89–1.00). About 31% were ER- and PgR-negative, and 69% were ER- and/or PgR-positive.

Conclusions

Contrary to most previous reports in other parts of sub-Saharan Africa, the majority of patients in Ethiopia are ER-positive rather than ER-negative. These findings are in line with low proportions of ER-negative BCs from East African immigrants within the SEER database, and they have clinical implications for management of BC patients in Ethiopia and other parts of sub-Saharan Africa where ER-status is not ascertained as part of routine management of the disease. Since the majority of patients showed ER-positive BC, Tamoxifen-therapy should be given to all patients even with unknown ER status.

Background

The cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin.

Methods

Cell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning.

Results

TRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines.

Conclusions

Our study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here.