Manganese Superoxide Dismutase Is a Promising Target for Enhancing Chemosensitivity of Basal-Like Breast Carcinoma

AIMS: Although earlier reports highlighted a tumor suppressor role for manganese superoxide dismutase (MnSOD), recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present article, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype, and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype.

RESULTS: Using MDA-MB-231 and BT549 as a model of basal breast cancer cell lines, we show that knockdown of MnSOD decreased the colony-forming ability and sensitized the cells to drug-induced cell death, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to down-regulate MnSOD expression in patients with basal breast carcinoma, we employed activation of the peroxisome proliferator-activated receptor gamma (PPARγ) to repress MnSOD expression; PPARγ activation significantly reduced MnSOD expression, increased chemosensitivity, and inhibited tumor growth. Moreover, as a proof of concept for the clinical use of PPARγ agonists to decrease MnSOD expression, biopsies derived from breast cancer patients who had received synthetic PPARγ ligands as anti-diabetic therapy had significantly reduced MnSOD expression. Finally, we provide evidence to implicate peroxynitrite as the mechanism involved in the increased sensitivity to chemotherapy induced by MnSOD repression.

INNOVATION AND CONCLUSION: These data provide evidence to link increased MnSOD expression with the aggressive basal breast cancer, and underscore the judicious use of PPARγ ligands for specifically down-regulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma.

MIR-433 Predicts poor response to chemotherapy in ovarian cancer patients by the induction of cellular senescence

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynaecological malignancy. Such mortality is predominantly associated with the development of an intrinsic and acquired resistance to chemotherapy, the lack of targeted therapies and the lack of biomarkers predicting response to standard treatment.

Our clinical data demonstrates that increased miR-433 expression in primary high grade serous OC (HGSOCs) is significantly associated with poor PFS (n=46, p=0.024). Interestingly, the IHC analysis of two miR-433 targets: MAD2 [1] and HDAC6 shows that low IHC levels of both proteins is also significantly associated with worse outcome (p=0.002 and 0.002 respectively; n=43). Additionally, the analysis of miR 433 in the publicly available TCGA dataset corroborates that high miR-433 is significantly correlated with worse OS for patients presenting with OC (n=558 and p=0.027). In vito, in a panel of OC cell lines, higher miR-433 and lower MAD2 and HDAC6 levels were associated with resistance to paclitaxel.

To further investigate the role of miR-433 in the cellular response to chemotherapy, we generated an OC cell line stably expressing miR-433 or miR-control. MTT viability assays and Western Blot analyses established that miR-433 cells were more resistant to paclitaxel treatment (50nM) compared to miR-controls. Importantly, we have shown for the first time that miR 433 induced senescence resulting in a chracteristic flattened morphology and down-regulation of phosphorylated Retinoblastoma (p Rb), a molecular marker of senescence. Surprisingly, miR 433 induced senescence was independent from two well recognised senescent drivers: namely p53/p21 and p16. To explore this further we performed an in silico analysis of seven microRNA platforms which indicated that miR 433 potentially targets Cyclin-dependent kinase CDK6, which promotes sustained phosphorylation of Rb and thus cell cycle progression. In vitro, the overexpression of pre-miR-433 resulted in diminished CDK6 expression demonstrating a novel interaction between miR-433 and CDK6.

In conclusion, this study demonstrates that high miR-433 expression predicts poor outcome in OC patients by putatively rendering OC cells resistant to paclitaxel treatment through the induction of cellular senescence identifying this microRNA as a potential marker of chemoresponse.

Psychosocial interventions to improve quality of life and emotional wellbeing in newly diagnosed cancer patients

Title
Psychosocial interventions to improve quality of life and emotional wellbeing for recently diagnosed cancer patients.

Background
Despite clear guidelines recommending the provision of emotional support for cancer patients, we do not know how best to address psychological distress in this group.

Aim
To assess the effects of psychosocial interventions to improve quality of life (QoL) and general psychological distress newly diagnosed cancer patients.

Methods
We searched electronic sources for RCTs of psychosocial interventions or ‘talking therapies’ with individual newly diagnosed cancer patients. Only trials measuring QoL and general psychological distress were included. Meta-analyses examined subgroups by outcome measurement, mode of delivery and discipline of trained helper.

Results
Thirty trials met the criteria. No significant effects were observed for QoL at 6-months (SMD 0.11; 95% CI -0.00 to 0.22) except when using cancer-specific measures (SMD 0.16; 95% CI 0.02 to 0.30). Sub-group analyses revealed that psycho-educational, nurse-delivered interventions improved QoL (SMD 0.23; 95% CI 0.04 to 0.43). General psychological distress as assessed by ‘mood measures’ improved (SMD - 0.81; 95% CI -1.44 to -0.18), but heterogeneity was a factor.

Discussion and conclusion
Psychosocial interventions vary in format and content, raising concerns about heterogeneity, despite appearing to have a beneficial impact on cancer-specific QoL and mood. Future research should concentrate on screening for emotional support needs and identifying common elements within interventions that are of value. Authors should carefully select outcome measures that are appropriately sensitive to change.

Psychosocial interventions to improve quality of life and emotional wellbeing in newly diagnosed cancer patients

Title
Psychosocial interventions to improve quality of life and emotional wellbeing for recently diagnosed cancer patients.

Background
Despite clear guidelines recommending the provision of emotional support for cancer patients, we do not know how best to address psychological distress in this group.

Aim
To assess the effects of psychosocial interventions to improve quality of life (QoL) and general psychological distress newly diagnosed cancer patients.

Methods
We searched electronic sources for RCTs of psychosocial interventions or ‘talking therapies’ with individual newly diagnosed cancer patients. Only trials measuring QoL and general psychological distress were included. Meta-analyses examined subgroups by outcome measurement, mode of delivery and discipline of trained helper.

Results
Thirty trials met the criteria. No significant effects were observed for QoL at 6-months (SMD 0.11; 95% CI -0.00 to 0.22) except when using cancer-specific measures (SMD 0.16; 95% CI 0.02 to 0.30). Sub-group analyses revealed that psycho-educational, nurse-delivered interventions improved QoL (SMD 0.23; 95% CI 0.04 to 0.43). General psychological distress as assessed by ‘mood measures’ improved (SMD - 0.81; 95% CI -1.44 to -0.18), but heterogeneity was a factor.

Discussion and conclusion
Psychosocial interventions vary in format and content, raising concerns about heterogeneity, despite appearing to have a beneficial impact on cancer-specific QoL and mood. Future research should concentrate on screening for emotional support needs and identifying common elements within interventions that are of value. Authors should carefully select outcome measures that are appropriately sensitive to change.

The fate of chemoresistance in triple negative breast cancer (TNBC)

Background: Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. 
Scope of Review: How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. 
Major conclusions: Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. 
General Significance: Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy

Dietary fat and breast cancer mortality: a systematic review and meta-analysis

Background: The influence of dietary fat upon breast cancer mortality remains largely understudied despite extensive investigation into its influence upon breast cancer risk 

Objective: To conduct meta-analyses of studies to clarify the association between dietary fat and breast cancer mortality Design: MEDLINE and EMBASE were searched for relevant articles published up to March 2012. Risk of all-cause or breast cancer specific death was evaluated by combining multivariable adjusted estimates comparing highest versus lowest categories of intake; and per 20 gram increase in intake of total and/or saturated fat (g/day) using random-effects meta-analyses. 

Results: Fifteen prospective cohort studies investigating total fat and/or saturated fat intake (g/day) and breast cancer mortality were included. There was no difference in risk of breast cancer specific death (n = 6; HR = 1.14; 95% CI: 0.86, 1.52; P = 0.34) or all cause death (n = 4; HR = 1.73; 95% CI: 0.82, 3.6; P = 0.15) for women in the highest versus lowest category of total fat intake. Breast cancer specific death (n = 5; HR = 1.63; 95% CI: 1.19, 2.24; p <0.01) was higher for women in the highest versus lowest category of saturated fat intake. 

Conclusions: These meta-analyses have shown that saturated fat intake negatively impacts upon breast cancer survival.

BRCA1--conductor of the breast stem cell orchestra:the role of BRCA1 in mammary gland development and identification of cell of origin of BRCA1 mutant breast cancer

Breast cancer treatment has been increasingly successful over the last 20 years due in large part to targeted therapies directed against different subtypes. However, basal-like breast cancers still represent a considerable challenge to clinicians and scientists alike since the pathogenesis underlying the disease and the target cell for transformation of this subtype is still undetermined. The considerable similarities between basal-like and BRCA1 mutant breast cancers led to the hypothesis that these cancers arise from transformation of a basal cell within the normal breast epithelium through BRCA1 dysfunction. Recently, however, a number of studies have called this hypothesis into question. This review summarises the initial findings which implicated the basal cell as the cell of origin of BRCA1 related basal-like breast cancers, as well as the more recent data which identifies the luminal progenitor cells as the likely target of transformation. We compare a number of key studies in this area and identify the differences that could explain some of the contradictory findings. In addition, we highlight the role of BRCA1 in breast cell differentiation and lineage determination by reviewing recent findings in the field and our own observations suggesting a role for BRCA1 in stem cell regulation through activation of the p63 and Notch pathways. We hope that through an increased understanding of the BRCA1 role in breast differentiation and the identification of the cell(s) of origin we can improve treatment options for both BRCA1 mutant and basal-like breast cancer subgroups.

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.

Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.

Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.

Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Inter- and Intrafraction Target Motion in Highly Focused Single Vocal Cord Irradiation of T1a Larynx Cancer Patients

PURPOSE: The purpose of this study was to verify clinical target volume-planning target volume (CTV-PTV) margins in single vocal cord irradiation (SVCI) of T1a larynx tumors and characterize inter- and intrafraction target motion.

METHODS AND MATERIALS: For 42 patients, a single vocal cord was irradiated using intensity modulated radiation therapy at a total dose of 58.1 Gy (16 fractions × 3.63 Gy). A daily cone beam computed tomography (CBCT) scan was performed to online correct the setup of the thyroid cartilage after patient positioning with in-room lasers (interfraction motion correction). To monitor intrafraction motion, CBCT scans were also acquired just after patient repositioning and after dose delivery. A mixed online-offline setup correction protocol ("O2 protocol") was designed to compensate for both inter- and intrafraction motion.

RESULTS: Observed interfraction, systematic (Σ), and random (σ) setup errors in left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions were 0.9, 2.0, and 1.1 mm and 1.0, 1.6, and 1.0 mm, respectively. After correction of these errors, the following intrafraction movements derived from the CBCT acquired after dose delivery were: Σ = 0.4, 1.3, and 0.7 mm, and σ = 0.8, 1.4, and 0.8 mm. More than half of the patients showed a systematic non-zero intrafraction shift in target position, (ie, the mean intrafraction displacement over the treatment fractions was statistically significantly different from zero; P<.05). With the applied CTV-PTV margins (for most patients 3, 5, and 3 mm in LR, CC, and AP directions, respectively), the minimum CTV dose, estimated from the target displacements observed in the last CBCT, was at least 94% of the prescribed dose for all patients and more than 98% for most patients (37 of 42). The proposed O2 protocol could effectively reduce the systematic intrafraction errors observed after dose delivery to almost zero (Σ = 0.1, 0.2, 0.2 mm).

CONCLUSIONS: With adequate image guidance and CTV-PTV margins in LR, CC, and AP directions of 3, 5, and 3 mm, respectively, excellent target coverage in SVCI could be ensured.