Oncotarget

Oncotarget: IQGAP1 control of centrosome function defines variants of breast cancer

The cover for issue 26 of Oncotarget features Figure 6, "Mislocalization of IQGAP1-BRCA1 in human TNBC tumors phenocopies the dominant mutants and the TNBC cells," by Osman, et al. and reported that IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown.

Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation.

TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting the clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways.

The authors discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer.

These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine

Dr. Mahasin A. Osman from The Department of Medicine, Division of Oncology, Health Sciences Campus at The University of Toledo as well as The Department of Molecular Pharmacology, Physiology and Biotechnology, Division of Biology and Medicine at Warren Alpert Medical School of Brown University said, “The triple-negative breast cancer (TNBC) is a highly heterogeneous group of diseases defined by absence of expression of growth factor and hormonal receptors, and thus it is highly lethal due to lack of diagnostic markers and therapeutic targets.”

In vitro depletion of BRCA1 results in amplified centrosomes, a phenotype observed in early-stage tumors, including breast cancer, but how might wild type BRCA1 protein control centrosome amplification is unclear.

While increased centrosome size resulting from PCM expansion has been reported as abnormality in human tumors, increased centrosome number is observed in 20–30% of tumors that overexpress oncogenes or lack tumor suppressors like BRCA1.

Centrosome amplification has been associated with high-grade tumors and poor prognosis and was suggested as a biomarker for advanced cancer.

Expression of dominant active mutants of IQGAP1 associates with amplified centrosomes while the expression of dominant-negative mutants associates with increased centrosome size.

The authors discuss a model whereby IQGAP1 acts as a signaling scaffold in the centrosome and influences centrosome protein transport, dysfunction of which underlie centrosome aberrations in cancer thereby presenting IQGAP1 as a common target in variants of TNBC, amenable to personalized medicine.

The Rotelli Research Team concluded in their Oncotarget Research Paper that taken together, the findings of this study underscore the importance of the delicate balance of expression, localization and/or modification of IQGAP1-BRCA1 and centrosome proteins in cell homeostasis and support that IQGAP1 influences BRCA1 transport or anchorage.

IQGAP1 may serve as a regulatory scaffold for BRCA1 and other centrosomal proteins to regulate their stability or transport between the nucleus and the centrosome, a mechanism by which it modulates nuclear-centrosome crosstalk during the cell cycle and thus regulates cell proliferation.

Furthermore, as IQGAP1 has been implicated in various carcinomas, the mechanisms discussed here likely apply to a wide range of carcinoma, thus presenting IQGAP1 as a non-organ-specific clinical target amenable to precision medicine

DOI - https://doi.org/10.18632/oncotarget.27623

Full text - https://www.oncotarget.com/article/27623/text/

Correspondence to - Mahasin A. Osman - [email protected], [email protected].

Keywords - IQGAP1, BRCA1, β-catenin, MNK1, triple negative breast cancer

Volume 11, Issue 25 of @Oncotarget reported that Administration of landiolol hydrochloride was found to be associated with reduced incidence of atrial fibrillation after esophagectomy for esophageal cancer in our previous randomized controlled trial.

Between March 2014 and January 2016, 100 patients with esophageal cancer were registered in an RCT trial and randomly allocated to receive either administration of landiolol or a placebo.

The authors analyzed data from this RCT to better understand the effect of postoperative AF and severe associated complications on overall survival after esophagectomy for cancer.

In multivariate analysis, high stage alone was an independent prognostic factor for esophageal cancer patients the following esophagectomy.

Dr. Toshiyasu Ojima from The Wakayama Medical University said, "Esophagectomy is considered the optimum treatment against esophageal cancers."

The incidence of major postoperative complications in our previous study increased in patients that developed new-onset AF following subtotal esophagectomy.

The effect of postoperative AF on long-term survival following esophagectomy is therefore controversial.

Severe postoperative complications may make patients with esophageal cancer less likely to survive over the long term.

Patients with esophageal cancer but without severe postoperative complications have been shown to have better long-term survival than patients with complications.

The authors also evaluate the influence of severe postoperative complications on overall survival and whether prophylactic administration of landiolol hydrochloride directly influences prolonged survival in patients with esophageal cancer.

The Ojima Research Team concluded in their Oncotarget Research Paper, "new-onset AF and other severe complications were not associated with poorer long-term survival after esophagectomy. In addition, administration of landiolol hydrochloride after esophagectomy did not contribute to the prolonged OS of patients with esophageal cancer."

DOI - https://doi.org/10.18632/oncotarget.27643

Full text - https://www.oncotarget.com/article/27643/text/

Correspondence to - Toshiyasu Ojima - [email protected]

Keywords - esophageal cancer, atrial fibrillation, landiolol, randomized controlled trial, complication

About Oncotarget

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Volume 11, Issue 25 of @Oncotarget reported that to examine the role of RSK in AML, the authors analyzed apoptosis and the cell cycle profile following treatment with BI-D1870, a potent inhibitor of RSK. BI-D1870 treatment increased the G2/M population and induced apoptosis in Acute Myeloid Leukemia cell lines and patient Acute Myeloid Leukemia cells.

Therefore, the authors investigated whether BI-D1870 potentiates the anti-leukemic activity of vincristine by targeting mitotic exit.

Combination treatment of BI-D1870 and vincristine synergistically increased mitotic arrest and apoptosis in acute leukemia cells.

These data show that BI-D1870 induces apoptosis of AML cells alone and in combination with vincristine through blocking mitotic exit, providing a novel approach to overcoming vincristine resistance in AML cells.

Dr. Kathleen M. Sakamoto from Stanford University School of Medicine said, "Acute myeloid leukemia (AML) is a genetically and phenotypically heterogeneous hematologic malignancy characterized by the accumulation of immature myeloid blasts with resultant peripheral blood cytopenia."

Treatment of cells with microtubule targeting agents, including paclitaxel and the vinca alkaloid vincristine, blocks the proper formation of the mitotic spindle through inhibition of microtubule dynamics, resulting in the prolonged mitotic arrest of cancer cells.

MTAs-treated mitotic arrested cells may undergo apoptosis in mitosis, however, the rapid degradation of Cyclin B due to an insufficient SAC leads to the mitotic slippage into tetraploid G1 stage in resistant cells.

Though vinca alkaloid microtubule-destabilizing compounds have shown clinical efficacy against various hematological malignancies and were included in combination chemotherapy of the VAPA study, they are not currently used in induction chemotherapy for AML due to their high toxicity against lymphoid cells and rapid degradation by myeloperoxidase in AML cells.

In this study, they demonstrate that BI-D1870, a potent inhibitor of RSK, induces mitotic arrest, and apoptosis in AML cells without inhibiting CDC2 and CDC25C. Furthermore, BI-D1870 synergizes with vinca alkaloid vincristine in AML cells, suggesting that inhibition of mitotic exit with BI-D1870 could be a promising novel approach for AML therapy in combination with MTAs.

The Sakamoto Research Team concluded in their Oncotarget Research Paper that BI-D1870 is a reversible pan-RSK inhibitor, showing > 500-fold higher activity for RSK than other AGC kinases.

BI-D1870 also inhibits the activity of PLK1, Aurora-B, MELK, PIM3, MST2, and GSK3β at higher concentrations than for RSK. BI-D1870 and BRD7389 have been reported to inhibit proliferation and significantly increase the G2/M population in melanoma cells.

BI-D1870 does not have proper physicochemical properties for clinical application.

Future structure-activity relationships study for BI-D1870 is required to improve solubility and pharmacokinetic profiles for in vivo preclinical and clinical studies.

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DOI - https://doi.org/10.18632/oncotarget.27630

Full text - https://www.oncotarget.com/article/27630/text/

Correspondence to - Kathleen M. Sakamoto - [email protected]

Keywords - acute myeloid leukemia, BI-D1870, RSK, vincristine, spindle assembly checkpoint

About Oncotarget

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Volume 11 Issue 25 of @Oncotarget reported that Indoximod has shaped the understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood.

Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation.

Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor, which controls transcription of several genes in response to different ligands including kynurenine.

Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells.

Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the Ah R. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme.

Dr. Erik L. Brincks from NewLink Genetics Corporation as well as Lumos Pharma, Inc. said "Indoleamine 2,3-dioxygenase (IDO1) plays an important role in the regulation of acquired local and peripheral immune tolerance in normal and pathological scenarios."

In cancer, IDO1 can be expressed either directly by the tumor cells or induced indirectly in host antigen presenting cells by the tumor.

IDO1 expression by tumor cells has been associated with significantly worse clinical prognosis and reduced survival in malignant melanoma, pancreatic cancer, ovarian cancer, both pediatric and adult acute myelogenous leukemia, colorectal cancer, prostate cancer, endometrial cancer, and others.

The cellular pharmacodynamic effects of IDO1 activity include the inhibition of antigen-specific CD8+ T cell proliferation, stimulation of differentiation of na�ve CD4+ T cells to Fox P3+ regulatory T cells, the activation of Tregs, and the recruitment of MDSC to the tumor.

Both isomers are capable of restoring T-cell proliferation in an MLR assay with IDO+ dendritic cells as the stimulator cells, or in syngeneic antigen-dependent T-cell proliferation assays using IDO+ dendritic cells isolated from tumor-draining lymph nodes.

L1m T is a competitive inhibitor and substrate of IDO1 enzymatic activity in cell-free assays using purified recombinant IDO1 enzyme, and in tumor cells treated with INFγ or in tumor cell lines transfected with expression vectors that encode IDO1 under the control of an heterologous promoter.

The Brincks Research Team concluded in their Oncotarget Research Paper that these effects are independent on the Trp metabolizing activity of IDO and/or TDO but happen to oppose the effects of the enzymatic activity of IDO and TDO by multiple mechanisms that act on cell types commonly affected by the IDO and TDO pathways.

Indoximod creates a Trp-sufficiency signal which leads to reactivation of MAP4K3 which leads to activation of mTORC1 activity, thus opposing and bypassing the effects of Trp deprivation that lead to GCN2 activation and MAP4K3 and mTOR inactivation.

This effect requires a relatively high concentration of indoximod, is observed in both CD4+ and CD8+ T cells and leads to an increase in the proliferative capacity of activated effector and helper T cells.

This effect takes place at clinically relevant concentrations of indoximod and is independent of IDO/TDO activity or exogenous Kyn, though it happens to oppose the Kyn/Ah R effects on T cell differentiation.

Full text - https://www.oncotarget.com/article/27646/text/

Volume 11 Issue 25 of @Oncotarget reported that the authors aimed to characterize the bacteriome, mycobiome, and mycobiome-bacteriome interactions of oral wash in Head and neck squamous cell carcinoma, or HNSCC, patients and to determine if they are distinct from those of the oral wash of matched non-Head and neck squamous cell carcinoma patients.

Oral wash samples were collected from 46 individuals with HNSCC and 46 controls for microbiome analyses.

A number of organisms were identified as being differentially abundant between oral wash samples from patients with HNSCC and oral wash samples from those without HNSCC. Of note, strains of Candida albicans and Rothia mucilaginosa were differentially abundant and Schizophyllum commune was depleted in those with HNSCC compared to oral wash from those without HNSCC. Our results suggest that the oral cavity of HNSCC patients harbors unique differences in the mycobiome, bacteriome, and microbiome interactions when compared to those of control patients.

Dr. Charis Eng from The Cleveland Clinic as well as The Case Western Reserve University School of Medicine said, "Head and neck squamous cell carcinoma (HNSCC) refers to cancer arising from the squamous epithelium of the oral cavity, pharynx, nasopharynx, and larynx."

Not all patients with these risk factors develop HNSCC, and some patients with HSNCC lack these risk factors.

There is, therefore, a need to identify additional risk factors to better predict which patients, particularly among those at high risk, will develop HNSCC. The oral microbiome contains not only bacterial communities but also fungal communities comprising the oral mycobiome.

Fungal communities have the potential not only to independently influence the environment of the oral cavity but also to interact with oral bacterial communities.

Therefore, the authors sought to identify and characterize differences in the bacteriome and mycobiome profiles of patients with HNSCC versus healthy cancer-free patients, using oral wash as template biospecimen.

The Eng Research Team concluded in their Oncotarget Research Paper that they found inter and intra-kingdom correlations within the oral wash.

Although the composition of the clusters within networks appeared largely similar between case and control oral wash, there were some interactions that differed.

A positive relationship between two organisms could suggest that they occupy similar niches or even that they share a symbiotic relationship.

A negative relationship, by contrast, could point to two organisms that either compete against each other through varying means.

They went on to note multiple interactions that were opposing when considering case oral wash versus control oral wash suggests not only changes in the composition of the microbiome but also in how members of the microbiome interact with each other in HNSCC patients.

The relationship between Alloscardovia and Candida, for example, was negative, in case oral wash but positive in control oral wash.

Such shifts could signal the presence of HNSCC in an oral wash based screening tool for Head and neck squamous cell carcinoma.

DOI - https://doi.org/10.18632/oncotarget.27629

Full text - https://www.oncotarget.com/article/27629/text/

Correspondence to - Charis Eng - [email protected]

Keywords - microbiome, bacteriome, mycobiome, head and neck squamous cell carcinoma, cancer

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Volume 11, Issue 25 of @Oncotarget reported that the present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells.

The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression.

Wild-type p53 stimulated INSR promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53.

Mutant p53 strongly stimulated INSR promoter.

Furthermore, p53 directly binds to the INSR promoter in cells with a disrupted IGF1R.

Dr. Haim Werner from Tel Aviv University said, "The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life."

The classical view that emerged following the cloning and characterization of the INSR and IGF1R genes in the mid-1980s postulated that activation of INSR by insulin leads, predominantly, to metabolic activities.

One of the cardinal questions still in need of a biologically plausible rationalization is why the INSR and IGF1R, even though they share the majority of their downstream cytoplasmic targets and signaling pathways, are yet responsible for mediating distinct physiological and pathological activities.

Given the emerging evidence of proliferative and potentially anti-apoptotic actions of INSR, the authors investigated in the present paper the regulation of the INSR gene promoter by wild-type and mutant p53 in breast cancer cells.

Using cells with specific disruption of the INSR or IGF1R, the authors also assessed the effect of each one of these signaling pathways on p53 expression and activity.

The data indicate that: activation of p53 is negatively regulated by IGF1R, as indicated by the augmented phosphorylation of p53 in IGF1R-KD cells; p53 directly binds to the INSR promoter region in cells with a disrupted IGF1R; wild-type p53 represses INSR promoter activity in IGF1R-KD and INSR-KD cells while enhancing promoter activity in control cells; mutant p53 stimulates INSR promoter activity in breast cancer cells.

The Werner Research Team concluded in their Oncotarget Research Paper, "we have presented evidence that the INSR gene constitutes a downstream target for p53 action. Whereas wild-type p53 stimulated INSR promoter activity in control MCF7 cells, disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by wild-type p53. Mutant, oncogenic versions of p53, for the most part, strongly stimulated INSR promoter. In addition, p53 exhibits direct binding to the INSR promoter region in cells with a disrupted IGF1R. Taken together, data presented here identifies complex functional and physical interactions between p53 and the INSR pathway. The clinical implications of this interplay in breast cancer needs to be critically assessed."

DOI - https://doi.org/10.18632/oncotarget.27645

Full text - https://www.oncotarget.com/article/27645/text/

Correspondence to - Haim Werner - [email protected]

Keywords - insulin, insulin-like growth factor-1 (IGF1), insulin receptor, IGF1 receptor, p53

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Volume 11 Issue 25 of @Oncotarget reported that this study aimed to define the mutation profile of SUM in Caucasians.

Next-generation sequencing-based genomic analysis was used to identify frequently mutated loci in 50 cancer-related genes in 31 SUM primary tumors.

The most abundant mutations in SUM were found in KIT – in 13% of cases and NRAS – also in 13%, while BRAF - only in 3% of cases.

The authors' findings confirmed a high frequency of KIT and NRAS mutations in SUM, as well as a low incidence of BRAF mutations.

They reported novel KRAS, CTNNB1, TP53, ERBB2, and SMAD4 mutations in SUM.

Dr. Aneta Borkowska from The Maria Sklodowska-Curie National Research Institute of Oncology said "Across all human cancers, cutaneous malignant melanoma (MM) genome has one of the highest prevalence of somatic mutations."

At the same time, NRAS mutations are detected in approximately 20% of MM and are more commonly reported in melanomas developing in the skin with chronic sun exposure.

WHO Classification of Skin Tumours recognizes the most common acral melanoma histotype is acral lentiginous melanoma, followed by nodular cutaneous melanoma and superficial spreading melanoma.

Cutaneous MM located on the acral part of extremities - hand and foot melanoma - comprises a rare group within all melanomas in Caucasians.

Whole-genome sequencing study shown that structural changes and mutational signature of acral melanomas were dominated by different than other MMs sites.

SUM seems to be not related to sun exposure, however, in Australian Melanoma Genome Project UVR signatures on acral melanomas occurred most frequently in subungual parts.

The Borkowska Research Team concluded in their Oncotarget Research Paper, "Our study offers new insights into the genetics SUM subtype, for understanding pathogenesis and providing potential biomarkers for future studies. Molecular testing is now widely used in patients with advanced melanoma in the process of therapeutic decisions. Mutations reported in melanoma cells provide starting points for the development of the rational design of novel therapies, including immunotherapy agents. They also may provide to find the molecular pathogenesis and natural history of subtypes of this heterogeneous disease. We confirmed that SUM have different than other cutaneous melanomas genetic profile, which due to its rareness and lack of studies should be subjected to further analyzes in multicenter studies."

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DOI - https://doi.org/10.18632/oncotarget.27642

Full text - https://www.oncotarget.com/article/27642/text/

Correspondence to - Aneta Borkowska - [email protected]

Keywords - melanoma, acral melanoma, subungual melanoma, nail apparatus melanoma, SMAD4

About Oncotarget

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The cover for issue 24 of Oncotarget features Figure 4, "Cancer-specific survival curves based on GNRI according to pTNM stage," by Hirahara, et al.

Volume 11 Issue 24 of @Oncotarget reported that this study aimed to evaluate the relationship between preoperative Geriatric Nutritional Risk Index and long-term outcomes in elderly gastric cancer patients.

In the univariate analyses, OS was significantly associated with the American Society of Anesthesiologists Physical Status, tumor size, tumor differentiation, pathological stage, carcinoembryonic antigen, C-reactive protein, postoperative complications, and GNRI, whereas in the univariate analyses of CSS, ASA-PS, tumor size, tumor differentiation, pathological stage, CEA, postoperative adjuvant chemotherapy, and Geriatric Nutritional Risk Index were significantly associated with poor prognosis.

In the multivariate analysis, ASA-PS, tumor differentiation, pathological stage, and GNRI were significant independent prognostic factors of OS, whereas ASA-PS, pathological stage, and CEA were significant independent prognostic factors of CSS. Geriatric Nutritional Risk Index is significantly associated with OS and CSS in elderly gastric cancer patients and is an independent predictor of OS. It is a simple, cost-effective, and promising nutritional index for predicting OS in elderly patients.

Dr. Noriyuki Hirahara from The Department of Digestive and General Surgery at Shimane University Faculty of Medicine said "The tumor–node–metastasis (TNM) staging has been the global standard for estimating cancer cell dissemination."

The impact of the nutritional status on the outcome of cancer patients has been intensively studied in recent years, and several assessment tools have been proposed for nutritional screening.

However, the usefulness of these tools has not been fully evaluated in elderly patients.

The geriatric nutritional risk index was developed as a simple and objective nutritional assessment tool for hospitalized elderly patients based on their body weight and serum albumin level.

Therefore, the authors believe that the Geriatric Nutritional Risk Index accurately reflects the nutritional status of elderly cancer patients who are at risk of malnutrition because of their physiological frailty and vulnerability.

The principal aim of this study was to evaluate the prognostic significance of the preoperative Geriatric Nutritional Risk Index for estimating the postoperative outcomes of elderly gastric cancer patients.

The Hirahara Research Team concluded in their Oncotarget Research Paper that in Japan, which has an aging society, an individualized treatment strategy for gastric cancer is indispensable because there are many deaths caused by other diseases.

Recently, sarcopenia has been reported to affect the incidence of adverse events with chemotherapy and the continuation of treatment, leading to a worse prognosis.

Sarcopenia, the age-related loss of skeletal muscle mass and strength, was identified based on cross-sectional computed tomography images at the L3 level.

However, the Geriatric Nutritional Risk Index can be easily calculated from routine laboratory data and physical measurements.

The clinical significance of GNRI, as an indicator of OS, will be increasingly important in the future.

DOI - https://doi.org/10.18632/oncotarget.27635

Full text - https://www.oncotarget.com/article/27635/text/

Correspondence to - Noriyuki Hirahara - [email protected]

Keywords - geriatric nutritional risk index, overall survival, cancer-specific survival, gastric cancer, elderly patients

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open-access biomedical journal covering research on all aspects of oncology.

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Volume 11, Issue 22 of Oncotarget reported that despite relevant medical advancements, metastatic breast cancer remains an incurable disease.

HER2 signaling conditions tumor behavior and treatment strategies of HER2 expressing breast cancer.

Cancer treatment guidelines uniformly identify dual blockade with pertuzumab and trastuzumab plus a taxane as best first line and trastuzumab emtansine as a preferred second-line choice.

However, there is no prospectively designed available study focusing on the sequence and outcomes of patients treated with T-DM1 following the triplet.

In the following report, data concerning a wide series of patients treated in a real-life setting are presented.

Results obtained in terms of response and median progression-free survival suggests a significant role for T-DM1 in disease control of metastatic HER2 expressing breast cancer.

Dr. Salvatore Del Prete from the Medical Oncology Unit “San Giovanni di Dio” Hospital, Frattamaggiore as well as Dr. Liliana Montella from the Medical Oncology Unit “Santa Maria delle Grazie” Hospital said, "From the 80s, Human Epidermal Growth Factor Receptor 2 (HER2) signaling was increasingly recognized as pivotal in tumor growth of HER2 expressing breast cancer. HER2 expression is limited to a proportion (15–20%) of breast cancer; however, HER2 conditions tumor behavior and addresses treatment strategies."

Currently available guidelines in metastatic HER2 positive breast cancer design a sequence of treatment with first-line double blockade with trastuzumab plus pertuzumab and a taxane according to Cleopatra trial results and second-line treatment with trastuzumab emtansine enforced by Emilia trial results and, then, lapatinib plus capecitabine.

The reduced toxicity of T-DM1 in the second and later lines of treatment together and the high rates of activity and efficacy are determinant in choosing treatment for a patient candidate to a prolonged time on treatment.

On February 22, 2013, the Food and Drug Administration approved T-DM1 for use as a single agent in the treatment of patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane.

Such results induced FDA on May 3, 2019, to approve T-DM1 for the adjuvant treatment of patients with HER2-positive early breast cancer treated with neoadjuvant taxane and trastuzumab-based treatment and having a residual invasive disease in the breast or axilla at the surgery.

In the present study, data coming from different centers concerning patients with HER2 positive metastatic breast cancer treated with second-line T-DM1 following trastuzumab and pertuzumab were collected and evaluated.

The Del Prete/Montella Research Team concluded in their Oncotarget Research Article that despite the increased rate of survival of metastatic breast cancer patients overall, a rate of patients is lost at any line of therapy.

In two different studies concerning patients series treated predominantly before 2010, 3% and 26% of patients reached the goal of third-line treatment.

This evidence underscores the need to give our patients the best treatment as early as possible.

Summarizing, the available evidence is substantially in favor of the choice of T-DM1 in the treatment of HER2 breast cancer at second and later lines.

DOI - https://doi.org/10.18632/oncotarget.27603

Full text - https://www.oncotarget.com/article/27603/text/

Correspondence to - Salvatore Del Prete - [email protected] and Liliana Montella - [email protected]

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Volume 11, Issue 22 of Oncotarget reported that the goal of this study was to explore the involvement of mi RNAs in beneficial effects exerted by physical activity in breast cancer prevention.

The levels of extracellular mi RNAs were evaluated in blood plasma before and after structured exercise by means of microarray analysis of 1,900 mi RNAs identifying mostly modulated mi RNAs. The different expressions of two mi RNAs involved in breast cancer progression, i. e. up-regulation of mi R-206 and down-regulation of anti-miR-30c, were the most striking effects induced by exercise.

The biological effects of these mi RNAs were investigated in MCF-7 human breast cancer cells.

The evaluation of these mi RNAs in the blood can be used as non-invasive biomarkers for breast cancer prevention.

Dr. Alessandra Pulliero from the Department of Health Sciences at The University of Genoa said, "The relevance of structured exercise for public health has been addressed by the World Health Organization, and its lack is estimated to be the main risk factor for 21–25% of breast and colon cancer cases, 27% of diabetes cases, and 30% of ischemic heart disease cases."

Breast cancer survivors engaging in structured exercise increase the drainage of lymph from their upper limbs, thereby decreasing the side effects of mastectomy, significantly lowering their risk of cancer relapse and improving their immune functions.

Structured exercise improves insulin resistance, reduces hyperinsulinaemia and reduces the risk for diabetes, which could explain the link between increased structured exercise and reduced risk for these cancers.

Recent findings indicate that women with a history of breast cancer who engage in more than 9 metabolic equivalent h/week of structured exercise after a breast cancer diagnosis had a significantly lower risk of death or breast cancer recurrence than women who were physically inactive.

Incubation of MCF-7 estrogen-responsive breast cancer cells and MDA-MB-231 triple-negative breast cancer cells treated with post-exercise serum, from both healthy volunteers and operated cancer patients resulted in a reduction of breast cancer cell viability in comparison with breast cancer cells incubated with pre-exercise sera.

Accordingly, the authors analyzed circulating mi RNAs expression profiles before and after structured exercise and evaluated their potential anti-cancer properties in breast cancer cells.

The Pulliero Research Team concluded in their Oncotarget Research Article, "this study provides evidence that miRNA modulation is a specific molecular mechanism through which structured exercise exerts preventive effects against cancer. The possibility of using these two miRNAs for breast cancer prevention is of interest. MicroRNA as delivered by lipid nanoparticles has been already been effective in mice in preventing NNK induced lung cancer [46]. However, insofar no similar experiments exist as far as concern breast cancer prevention.

Moreover, the evaluation of miR-206 and anti-miR-30c levels in the blood of breast cancer patients could be useful as non-invasive biomarkers in guiding future strategies for cancer prevention."

DOI - https://doi.org/10.18632/oncotarget.27609

Full text - https://www.oncotarget.com/article/27609/text/

Correspondence to - Alessandra Pulliero - [email protected]

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