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BRIP1 overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes.

ABSTRACT: In Oman, breast cancer is most common, representing approximately more than 25% of all cancers in women. Relatively younger populations of patients (25-40 years) present surprisingly with an aggressive phenotype and advanced tumor stages. In this study, we investigated differential gene expressions in Luminal A, Luminal B, triple-negative and Her2+ breast cancer subtypes and compared data to benign tumor samples. We identified a potential candidate gene BRIP1, showing differential expression in the four breast cancer subtypes examined, suggesting that BRIP1 has the profile of a useful diagnostic marker, suitable for targeted therapeutic intervention. RT-qPCR and Western blotting analysis showed higher BRIP1 expression in luminal samples as compared to triple-negative subtype patient's samples. We further screened BRIP1 for eventual mutations/SNPs/deletions by sequencing the entire coding region. Four previously identified polymorphisms were detected, one within the 5'-UTR region (c.141-64G?>?A) and three in the BRCA-binding domain (c.2755T?>?C, c.2647G?>?A and c.3411T?>?C). Kaplan-Meier analysis revealed that patients with overexpression of BRIP1 displayed a poor survival rate (P?

SUBMITTER: Gupta I

PROVIDER: S-EPMC5744628 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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<i>BRIP1</i> overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes.

Gupta Ishita I Ouhtit Allal A Al-Ajmi Adil A Rizvi Syed Gauhar A SGA Al-Riyami Hamad H Al-Riyami Marwa M Tamimi Yahya Y

Endocrine connections 20171114 1

In Oman, breast cancer is most common, representing approximately more than 25% of all cancers in women. Relatively younger populations of patients (25-40 years) present surprisingly with an aggressive phenotype and advanced tumor stages. In this study, we investigated differential gene expressions in Luminal A, Luminal B, triple-negative and Her2+ breast cancer subtypes and compared data to benign tumor samples. We identified a potential candidate gene <i>BRIP1</i>, showing differential express ...[more]

PMID: 29138235

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Project description:IntroductionBreast cancer heterogeneity occurs as a consequence of the dysregulation of numerous oncogenic pathways as well as many non-genetic factors, including tumor microenvironmental stresses such as hypoxia, lactic acidosis, and glucose deprivation. Although the importance of these non-genetic factors is well recognized, it is not clear how to integrate these factors within the genetic framework of cancer as the next logical step in understanding tumor heterogeneity.MethodsWe report here the development of a series of gene expression signatures to measure the influences of microenvironmental stresses. The pathway activities of hypoxia, lactic acidosis, acidosis and glucose deprivation were investigated in a collection of 1,143 breast tumors, which have been separated into 17 breast tumor subgroups defined by their distinct patterns of oncogenic pathways. A validation dataset comprised of 547 breast tumors was also used to confirm the major findings, and representative breast cancer cell lines were utilized to validate in silico results and mechanistic studies.ResultsThrough the integrative pathway analysis of microenvironmental stresses and oncogenic events in breast tumors, we identified many known and novel correlations between these two sources of tumor heterogeneity. Focusing on differences between two human epidermal growth factor receptor 2 (HER2)-related subgroups, previously identified based on patterns of oncogenic pathway activity, we determined that these subgroups differ with regards to tumor microenvironmental signatures, including hypoxia. We further demonstrate that each of these subgroups have features consistent with basal and luminal breast tumors including patterns of oncogenic signaling pathways, expression of subtype specific genes, and cellular mechanisms that regulate the hypoxia response. Importantly, we also demonstrate that the correlated pattern of hypoxia-related gene expression and basal-associated gene expression are consistent across HER2-related tumors whether we analyze the tumors as a function of our pathway-based classification scheme, using the intrinsic gene list (ERBB2+), or based on HER2 IHC status. Our results demonstrate a cell lineage-specific phenomenon in which basal-like tumors, HER2-related tumors with high hypoxia, as well as normal basal epithelial cells express increased mRNA levels of HIF-1α compared to luminal types and silencing of HIF-1α results in decreased expression of hypoxia-induced genes.ConclusionsThis study demonstrates differences in microenvironmental conditions in HER2-related subgroups defined by distinct oncogenic pathway activities, and provides a mechanistic explanation for differences in the observed hypoxia response between these subgroups. Collectively, these data demonstrate the potential of a pathway-based classification strategy as a framework to integrate genetic and non-genetic factors to investigate the basis of tumor heterogeneity.

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.

Dataset Information

BRIP1 overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes.

Publications

<i>BRIP1</i> overexpression is correlated with clinical features and survival outcome of luminal breast cancer subtypes.

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