Lipid rafts, caveolae, and epidermal growth factor receptor family: friends or foes?

Lipid rafts are dynamic microdomains enriched with cholesterol and sphingolipids that play critical roles in cellular processes by organizing and concentrating specific proteins involved in signal transduction. The interplay between lipid rafts, raft-associated caveolae and the human epidermal growth factor receptors has significant implications in cancer biology, particularly in breast and gastric cancer therapy resistance. This review examines the structural and functional characteristics of lipid rafts, their involvement in EGFR and HER2 signaling, and the impact of lipid rafts/CXCL12/CXCR4/HER2 axis on bone metastasis. We also discuss the potential of targeting lipid rafts and caveolin-1 to enhance therapeutic strategies against HER2-positive cancers and the impact of co-localization of trastuzumab or antibody drug conjugates with caveolin-1 on therapy response. Emerging evidence suggests that disrupting lipid raft integrity or silencing caveolin-1, through several strategies including cholesterol-lowering molecules, can influence HER2 availability and internalization, enhancing anti-HER2 targeted therapy and offering a novel approach to counteract drug resistance and improve treatment efficacy.

Study of hormone receptors and epidermal growth factor expression in invasive breast cancers in a cohort of Western India.

The objective of study was to evaluate and correlate the pathological characteristics of breast cancer patients with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu) detected by immunohistochemistry and/or fluorescent in situ hybridization method. We have conducted 2 year study of 204 cases of breast cancer at HCG-Medisurge Hospitals, Ahmedabad from 2009 to 2011. Significant correlation was found in ER and PR expression whereas no correlation was found in hormonal receptors and Her2/neu expression. ER and PR positivity increased with advancing age in breast carcinoma patients while not affecting Her2/neu expression. The expression of hormone receptors were higher in infiltrating lobular carcinoma and infiltrating duct carcinoma subtypes of breast carcinoma as compared to other subtypes such medullary and in situ carcinoma. High-grade carcinoma patients were predominantly ER/PR negative and Her2/neu positive as compared to lower grade breast carcinoma whereas high-stage carcinoma patients were ER/PR positive and Her2/neu positive as compared to lower stage breast carcinoma.

Efficient expression, purification, and visualization by cryo-EM of unliganded near full-length HER3.

Biochemical analyses of membrane receptor kinases have been limited by challenges in obtaining sufficient homogeneous receptor samples for downstream structural and biophysical characterization. Here, we report a suite of methods for the efficient expression, purification, and visualization by cryo-electron microscopy (cryo-EM) of near full-length Human Epidermal Growth Factor Receptor 3 (HER3), a receptor tyrosine pseudokinase, in the unliganded state. Through transient mammalian cell expression, a two-step purification with detergent exchange into lauryl maltose neopentyl glycol (LMNG), and freezing devoid of background detergent micelle, we obtained ~6Å reconstructions of the ~60kDa fully-glycosylated unliganded extracellular domain of HER3 from just 30mL of suspension culture. The reconstructions reveal previously unappreciated extracellular domain dynamics and glycosylation sites.

Overexpression of PY1289-HER3 in sporadic pulmonary carcinoid from patients bearing MEN1 gene variants.

The present study aimed to investigate the expression of human epidermal growth factor receptors (HERs) (HER1/HER2/HER3/HER4) and their phosphorylated forms (p-HER1/p-HER2/p-HER3/p-HER4) in pulmonary carcinoids (PCs). HER and p-HER protein expression was assessed by immunohistochemistry on tissue microarrays in 37 specimens of sporadic PCs, 29 typical carcinoids (TCs) and 8 atypical carcinoids (ACs). When compared with the ACs, the TCs did not exhibit any differences in terms of HER/p-HER expression. The tumors of this study have previously been characterized for the expression of menin and the mutational status of menin 1 (MEN1), a gene strongly implicated in the pathogenesis of PCs. In the present study, it was found that the cytoplasmic ('disarrayed'), but not nuclear ('arrayed') expression of menin was positively correlated with HER3 (P=0.004), HER4 (P=0.015), p-HER1 (P=0.005), p-HER3 (P<0.001), and p-HER4 (P=0.001) expression. Moreover, HER3 and p-HER3 were found to be significantly more expressed in PCs with MEN1 variants, than in tumors with MEN1 wild-type (P=0.000 and P=0.025, respectively). These findings suggest the potential clinical use of HER inhibitors in the treatment of patients with PCs, particularly for individuals with p-HER3-positive PCs harboring MEN1 gene variants.

Comparative study between quantitative digital image analysis and fluorescence in situ hybridization of breast cancer equivocal human epidermal growth factor receptors 2 score 2(+) cases.

BACKGROUND: Optimization of workflow for breast cancer samples with equivocal human epidermal growth factor receptors 2 (HER2)/neu score 2(+) results in routine practice, remains to be a central focus of the on-going efforts to assess HER2 status. According to the College of American Pathologists/American Society of Clinical Oncology guidelines equivocal HER2/neu score 2(+) cases are subject for further testing, usually by fluorescence in situ hybridization (FISH) investigations. It still remains on open question, whether quantitative digital image analysis of HER2 immunohistochemistry (IHC) stained slides can assist in further refining the HER2 score 2(+). AIM OF THIS WORK: To assess utility of quantitative digital analysis of IHC stained slides and compare its performance to FISH in cases of breast cancer with equivocal HER2 score 2(+). MATERIALS AND METHODS: Fifteen specimens (previously diagnosed as breast cancer and was evaluated as HER 2(-) score 2(+)) represented the study population. Contemporary new cuts were prepared for re-evaluation of HER2 immunohistochemical studies and FISH examination. All the cases were digitally scanned by iScan (Produced by BioImagene [Now Roche-Ventana]). The IHC signals of HER2 were measured using an automated image analyzing system (MECES, www.Diagnomx.eu/meces). Finally, a comparative study was done between the results of the FISH and the quantitative analysis of the virtual slides. RESULTS: Three out of the 15 cases with equivocal HER2 score 2(+), turned out to be positive (3(+)) by quantitative digital analysis, and 12 were found to be negative in FISH too. Two of these three positive cases proved to be positive with FISH, and only one was negative. CONCLUSIONS: Quantitative digital analysis is highly sensitive and relatively specific when compared to FISH in detecting HER2/neu overexpression. Therefore, it represents a potential reliable substitute for FISH in breast cancer cases, which desire further refinement of equivocal IHC results.