Dataset Information

Protein co-expression networks identified from HOT lesions of ER+HER2-Ki-67high luminal breast carcinomas.

ABSTRACT: Patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative/Ki-67-high (ER+HER2-Ki-67high) luminal breast cancer have a worse prognosis and do not respond to hormonal treatment and chemotherapy. This study sought to identify disease-related protein networks significantly associated with this subtype, by assessing in-depth proteomes of 10 lesions of high and low Ki-67 values (HOT, five; COLD, five) microdissected from the five tumors. Weighted correlation network analysis screened by over-representative analysis identified the five modules significantly associated with the HOT lesions. Pathway enrichment analysis, together with causal network analysis, revealed pathways of ribosome-associated quality controls, heat shock response by oxidative stress and hypoxia, angiogenesis, and oxidative phosphorylation. A semi-quantitative correlation of key-protein expressions, protein co-regulation analysis, and multivariate correlation analysis suggested co-regulations via network-network interaction among the four HOT-characteristic modules. Predicted highly activated master and upstream regulators were most characteristic to ER-positive breast cancer and associated with oncogenic transformation, as well as resistance to chemotherapy and endocrine therapy. Interestingly, inhibited intervention causal networks of numerous chemical inhibitors were predicted within the top 10 lists for the WM2 and WM5 modules, suggesting involvement of potential therapeutic targets in those data-driven networks. Our findings may help develop therapeutic strategies to benefit patients.

SUBMITTER: Yamada K

PROVIDER: S-EPMC7814020 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Protein co-expression networks identified from HOT lesions of ER+HER2-Ki-67high luminal breast carcinomas.

Yamada Kimito K Nishimura Toshihide T Wakiya Midori M Satoh Eiichi E Fukuda Tetsuya T Amaya Keigo K Bando Yasuhiko Y Hirano Hiroshi H Ishikawa Takashi T

Scientific reports 20210118 1

Patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative/Ki-67-high (ER+HER2-Ki-67high) luminal breast cancer have a worse prognosis and do not respond to hormonal treatment and chemotherapy. This study sought to identify disease-related protein networks significantly associated with this subtype, by assessing in-depth proteomes of 10 lesions of high and low Ki-67 values (HOT, five; COLD, five) microdissected from the five tumors. Weighted correlation network an ...[more]

PMID: 33462336

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Project description:IntroductionKi-67 labeling index assessed by immunohistochemical assays has been shown useful in assessing the risk of recurrence for estrogen receptor (ER)-positive HER2-negative breast cancers (BC) and distinguishing Luminal A-like from Luminal B-like tumors. We aimed to assess the performance of the Ventana CONFIRM anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody.MethodsWe constructed a case-cohort design based on a random sample (n?=?679) of all patients operated on for a first primary, non-metastatic, ER-positive, HER2-negative BC at the European Institute of Oncology (IEO) Milan, Italy during 1998-2002 and all additional patients (n?=?303) operated during the same period, who developed an event (metastasis in distant organs or death due to BC as primary event) and were not included in the previous subset. Multivariable Cox proportional hazards regression with inverse subcohort sampling probability weighting was used to evaluate the risk of event according to Ki-67 (30-9) and derived intrinsic molecular subtype, using previously defined cutoff values, i.e., respectively 14% and 20%.ResultsKi-67 was?<?14% in 318 patients (32.4%), comprised between 14 and 19% in 245 patients (24.9%) and???20 in 419 patients (42.7%). At multivariable analysis, the risk of developing distant disease was 1.88 (95% CI 1.20-2.93; P?=?0.006) for those with Ki-67 comprised between 14 and 19%, and 3.06 (95% CI 1.93-4.84; P?<?0.0001) for those with Ki-67???20% compared to those with Ki-67?<?14%. Patients with Luminal B-like BC had an approximate twofold risk of developing distant disease (HR?=?1.91; 95% CI 1.35-2.71; P?=?0.0003) than patients with Luminal A-like BC defined using Ki-67 (30-9).ConclusionsKi-67 evaluation using the 30-9 rabbit monoclonal primary antibody was able to stratify patients with ER-positive HER2-negative BC into prognostically distinct groups. Ki-67 assessment, with strict adherence to the international recommendations, should be included among the clinically useful biological parameters for the best treatment of patients with BC.

Project description:Although most women with luminal breast cancer do well on endocrine therapy alone, some will develop fatal recurrence thereby necessitating the need to prospectively determine those for whom additional cytotoxic therapy will be beneficial. Categorical combinations of immunohistochemical measures of ER, PR, HER2, and KI67 are traditionally used to classify patients into luminal A-like and B-like subtypes for chemotherapeutic reasons, but this may lead to the loss of prognostically relevant information. Here, we compared the prognostic value of quantitative measures of these markers, combined in the IHC4-score, to categorical combinations in subtypes. Using image analysis-based scores for all four markers, we computed the IHC4-score for 2498 patients with luminal breast cancer from two European study populations. We defined subtypes (A-like (ER + and PR + : and HER2- and low KI67) and B-like (ER + and/or PR + : and HER2 + or high KI67)) by combining binary categories of these markers. Hazard ratios and 95% confidence intervals for associations with 10-year breast cancer-specific survival were estimated in Cox proportional-hazard models. We accounted for clinical prognostic factors, including grade, tumor size, lymph-nodal involvement, and age, by using the PREDICT-score. Overall, Subtypes [hazard ratio (95% confidence interval) B-like vs. A-like = 1.64 (1.25-2.14); P-value < 0.001] and IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.32 (1.20-1.44); P-value < 0.001] were prognostic in univariable models. However, IHC4-score [hazard ratio (95% confidence interval)/1 standard deviation = 1.24 (1.11-1.37); P-value < 0.001; likelihood ratio chi-square (LRχ2) = 12.5] provided more prognostic information than Subtype [hazard ratio (95% confidence interval) B-like vs. A-like = 1.38 (1.02-1.88); P-value = 0.04; LRχ2 = 4.3] in multivariable models. Further, higher values of the IHC4-score were associated with worse prognosis, regardless of subtype (P-heterogeneity = 0.97). These findings enhance the value of the IHC4-score as an adjunct to clinical prognostication tools for aiding chemotherapy decision-making in luminal breast cancer patients, irrespective of subtype.

Dataset Information

Protein co-expression networks identified from HOT lesions of ER+HER2-Ki-67high luminal breast carcinomas.

Publications

Protein co-expression networks identified from HOT lesions of ER+HER2-Ki-67high luminal breast carcinomas.

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