delta16HER2 splice variant and its role in HER2-overexpressing breast cancer

Deep insight on delta16HER2 splice variant and its role in HER2-overexpressing breast cancer

Serum HER2 Level Measured by Dot Blot: A Valid and Inexpensive Assay for Monitoring Breast Cancer Progression

Human epidermal growth factor receptor 2 (HER2) is one of the most important prognostic and predictive factors for breast cancer patients. Recently, serum HER2 ECD level of patients detected by enzyme-linked immunoabsorbent assay (ELISA) has been shown to predict tumor HER2 status and reveal its association with tumor progression, recurrence and poor prognosis. In this study, we established a new method, dot blot assay, to measure the serum HER2 level in breast cancer patients and further to evaluate the clinical value for monitoring breast cancer progression. We found that the serum HER2 level measured by dot blot assay was significantly correlated with tissue HER2 status in breast cancer patients (P = 0.001), and also significantly correlated with HER2 level measured by ELISA (P = 1.06×10−11). Compared with ELISA method, the specificity and sensitivity of dot blot assay were 95.3% and 65.0%, respectively. The serum HER2 levels of patients with grade III or ER-negative were higher than those with grade I–II (P = 0.004) and ER-positive (P = 0.033), respectively. Therefore, the novel dot blot method to detect serum HER2 level is a valid and inexpensive assay with potential application in monitoring breast cancer progression in clinical situations

Incidentally detected increased FDG uptake in bowel and its correlation with hystopathological data: our experience in a case series study.

When an intense intestinal FDG accumulation occurs, especially if focal, it can be referred to either physiological intestinal activity or bowel disease, thus leading to a radical change in patient's prognosis. Within a year, we recommended a colonoscopy to 103 of 7365 patients who were subjected to a total body FDG PET/CT. In a case-series study, we re-evaluated the patients and their lesions if already investigated with colonoscopy and biopsy. Only 18 patients were included in our study, but in none of them biopsy was negative and 3 adenocarcinomas, 8 adenomas, 5 inflammatory patterns, 1 hyperplastic polyp and 1 eosinophilic infiltrate were diagnosed. In 16 patients, no suspicion was present and diagnosis was absolutely incidental. Besides, among the three major groups (adenocarcinomas, adenomas and phlogosis), SUVmax values were significantly different. Adenocarcinomas are linked with high SUVmax values (ranging from 8.3 to 20.2) and large size (ranging from 26 to 43 mm). PET/CT sensitivity is low in detecting adenomas, being 71.4% if they are larger than 6 mm and 50% if SUVmax is lower than 4.9. SUVmax values in inflammatory lesions can range from 5.7 to 12. Colorectal cancer is still the second leading cause of cancer death, for this reason in many countries screening programs have been approved and colonoscopy is considered the golden standard. PET/CT cannot be considered as a screening test, but if it incidentally reveals intestinal abnormalities, this data cannot be underestimated and colonoscopy is highly recommended

Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab.

A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated "d16HER2 metagene" were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment

Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment

© 2019, International Society for Cellular Oncology. Purpose: Isothiocyanates elicit anticancer effects by targeting cancer stem cells (CSCs). Here, we tested the antitumor activity of phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive tumor models. Methods: We assessed the in vitro anticancer activity of PEITC, alone or combined with trastuzumab, in HER2-positive BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring their sphere forming efficiency (SFE). The expression of the human/rodent CSC biomarkers aldehyde-dehydrogenase (ALDH) and CD29High/CD24+/Sca1Low was evaluated by cytofluorimetric analysis. The expression of wild type HER2 (WTHER2), its splice variant d16HER2 and NOTCH was analysed by quantitative RT-PCR and Western blotting. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with MI6 tumor cells transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopy and immunohistochemistry were used to assess morpho-functional and metabolic profiles of treated versus untreated mice. Results: We found that PEITC significantly impaired the SFE of HER2-positive human cancer cells by decreasing their ALDH-positive compartments. The anti-CSC activity of PEITC was demonstrated by a reduced expression/activation of established cancer-stemness biomarkers. Similar results were obtained with MI6 cells, where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE. We also found that PEITC hampered the in vivo growth of MI6 nodules by inducing hemorrhagic and necrotic intra-tumor areas and, in combination with trastuzumab, by significantly reducing spontaneous tumor development in d16HER2 transgenic mice. Conclusions: Our results indicate that PEITC targets HER2-positive CSCs and that its combination with trastuzumab may pave the way for a novel therapeutic strategy for HER2-positive tumors