Ribavirin Treatment Effects on Breast Cancers Overexpressing eIF4E, a Biomarker with Prognostic Specificity for Luminal B-Type Breast Cancer

Abstract Objectives Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. Results Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

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Basal-like Breast Cancer—Characteristics, Risks, and Associations

Oncology & Hematology Review (US) ◽

10.17925/ohr.2012.08.1.26 ◽

2012 ◽

Vol 08 (01) ◽

pp. 26

Author(s):

Andrew Y Shuen ◽

William D Foulkes ◽

◽

Keyword(s):

Breast Cancer ◽

Massively Parallel Sequencing ◽

Target Identification ◽

Response To Therapy ◽

Breast Cancers ◽

Luminal A ◽

Luminal B ◽

Predictors Of Response ◽

Epidemiological Risk ◽

Basal Like Breast Cancer

Breast cancer is a heterogeneous disease. Gene expression profiling has demonstrated the existence of at least five ‘intrinsic’ subtypes: luminal A, luminal B, human epidermal growth factor-2 receptor (HER2), normal-like, and basal-like. While the estrogen receptor (ER), progesterone receptor (PR), and HER2 remain the most important prognostic markers and predictors of response to therapy, interrogating thousands of genetic transcripts more accurately captures the biological complexity and clinical heterogeneity of this disease. Target identification through massively parallel sequencing is likely to bear fruit in the coming years. Attention to basal-like breast cancers has grown substantially due to their generally poor prognosis, lack of targeted therapies, and connection withBRCA1-related cancers. In this article, we discuss the basal-like subgroup with respect to its cellular origins, relationship toBRCA1, and associated epidemiological risk factors.

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ER, PR, HER2, Ki-67 and CK5 in Early and Late Relapsing Breast Cancer—Reduced CK5 Expression in Metastases

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s10701 ◽

2013 ◽

Vol 7 ◽

pp. BCBCR.S10701 ◽

Cited By ~ 10

Author(s):

Kristiina Joensuu ◽

Marjut Leidenius ◽

Mia Kero ◽

Leif C. Andersson ◽

Kathryn B. Horwitz ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative ◽

Significant Risk ◽

Growth Factor Receptor ◽

Primary Therapy ◽

Breast Cancers ◽

Luminal A ◽

Ki 67 ◽

Luminal B

Breast cancer can recur even decades after the primary therapy. Markers are needed to predict cancer progression and the risk of late recurrence. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), proliferation marker Ki-67, and cytokeratin CK5 were studied to find out whether their expression or occurrence in subgroups of breast cancers correlated with the time of recurrence. The expression of HER2, ER, PR, Ki-67, and CK5 was studied by IHC in 72 primary breast cancers and their corresponding recurrent/metastatic lesions. The patients were divided into three groups according to the time of the recurrence/metastasis: before two years, after 5 years, and after 10 years. Based on their IHC profiles, the tumors were divided into surrogates of the genetically defined subgroups of breast cancers and the subtype definitions were as follows: luminal A (ER or PR+HER2–), luminal B (ER or PR+HER2+), HER2 overexpressing (ER–PR–HER2+), triple-negative (ER–PR–HER2–), basal-like (ER–PR–HER2–CK5+), non-classified (ER–PR–HER2–CK5–) and luminobasal (ER or PR+CK5+). In multivariate analysis, tumor size and HER2 positivity were a significant risk of early cancer relapse. The metastases showed a significantly lower CK5 expression. CK5 positivity distinguished triple negative tumors into rapidly and slowly recurring cancers. The IHC subtype ER or PR+HER2– luminal A presented a significantly lower risk of early tumor recurrence. Ki-67 expression denoted early-relapsing tumors and correlated linearly with tumor progression, since Ki-67 positivity declined gradually from early-relapsing toward late-recurring cancers.

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Evaluation of FGFR targeting in breast cancer through interrogation of patient-derived models

Breast Cancer Research ◽

10.1186/s13058-021-01461-4 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Nicole J. Chew ◽

Terry C. C. Lim Kam Sian ◽

Elizabeth V. Nguyen ◽

Sung-Young Shin ◽

Jessica Yang ◽

...

Keyword(s):

Breast Cancer ◽

Therapeutic Target ◽

Breast Cancer Subtype ◽

Breast Cancer Subtypes ◽

Cancer Tissue ◽

Breast Cancers ◽

Luminal A ◽

Tissue Samples ◽

Cancer Subtypes ◽

Luminal B

Abstract Background Particular breast cancer subtypes pose a clinical challenge due to limited targeted therapeutic options and/or poor responses to the existing targeted therapies. While cell lines provide useful pre-clinical models, patient-derived xenografts (PDX) and organoids (PDO) provide significant advantages, including maintenance of genetic and phenotypic heterogeneity, 3D architecture and for PDX, tumor–stroma interactions. In this study, we applied an integrated multi-omic approach across panels of breast cancer PDXs and PDOs in order to identify candidate therapeutic targets, with a major focus on specific FGFRs. Methods MS-based phosphoproteomics, RNAseq, WES and Western blotting were used to characterize aberrantly activated protein kinases and effects of specific FGFR inhibitors. PDX and PDO were treated with the selective tyrosine kinase inhibitors AZD4547 (FGFR1-3) and BLU9931 (FGFR4). FGFR4 expression in cancer tissue samples and PDOs was assessed by immunohistochemistry. METABRIC and TCGA datasets were interrogated to identify specific FGFR alterations and their association with breast cancer subtype and patient survival. Results Phosphoproteomic profiling across 18 triple-negative breast cancers (TNBC) and 1 luminal B PDX revealed considerable heterogeneity in kinase activation, but 1/3 of PDX exhibited enhanced phosphorylation of FGFR1, FGFR2 or FGFR4. One TNBC PDX with high FGFR2 activation was exquisitely sensitive to AZD4547. Integrated ‘omic analysis revealed a novel FGFR2-SKI fusion that comprised the majority of FGFR2 joined to the C-terminal region of SKI containing the coiled-coil domains. High FGFR4 phosphorylation characterized a luminal B PDX model and treatment with BLU9931 significantly decreased tumor growth. Phosphoproteomic and transcriptomic analyses confirmed on-target action of the two anti-FGFR drugs and also revealed novel effects on the spliceosome, metabolism and extracellular matrix (AZD4547) and RIG-I-like and NOD-like receptor signaling (BLU9931). Interrogation of public datasets revealed FGFR2 amplification, fusion or mutation in TNBC and other breast cancer subtypes, while FGFR4 overexpression and amplification occurred in all breast cancer subtypes and were associated with poor prognosis. Characterization of a PDO panel identified a luminal A PDO with high FGFR4 expression that was sensitive to BLU9931 treatment, further highlighting FGFR4 as a potential therapeutic target. Conclusions This work highlights how patient-derived models of human breast cancer provide powerful platforms for therapeutic target identification and analysis of drug action, and also the potential of specific FGFRs, including FGFR4, as targets for precision treatment.

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Performing Data Mining to Explain the Correlation between the BIRC5 Gene and Prognosis in Breast Cancer Patients

10.21203/rs.3.rs-33261/v1 ◽

2020 ◽

Author(s):

Hong Dongsheng ◽

Zhang YanFang ◽

Ye Ziqi ◽

Chen Jing ◽

Lu Xiaoyang

Keyword(s):

Breast Cancer ◽

Mrna Expression ◽

Cancer Patients ◽

Cancer Cell Line ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Luminal A ◽

Luminal B ◽

Kaplan Meier ◽

Er Positive

Abstract Background: Breast cancer is the most commonly malignant cancers in women, and BIRC5 has been found to be overexpressed in a variety of human tumors. Its expression is associated with the prognosis of many cancers. However, whether BIRC5 mRNA could be used as an independent prognostic factor for breast cancer remains inconsistent in previous studies.Methods: Altered BIRC5 expression in normal tissue relative to various tumor tissue and in breast cancer patients with different molecular subtypes, clinical outcomes and chemotherapy responses were examined using the Oncomine, GOBO and Kaplan-Meier plotter datasets.Results: We found that many breast cancers had increased BIRC5 mRNA expression, and GOBO analysis showed that triple-negative cell lines displayed highest BIRC5 mRNA expression levels in the breast cancer cell line panel. Moreover, BIRC5 high mRNA expression was significantly associated with longer relapse-free survival (RFS) in all breast cancer patients. In particular, sub analysis revealed that high mRNA expression of BIRC5 was significantly associated with better survival in ER positive (HR = 2.05, p = 1e-16), but not in ER negative breast cancer (HR = 1.24, p = 0.1), furthermore, the results also demonstrated that BIRC5 high expression was significantly associated with longer RFS in luminal A (HR = 1.51, p = 3.1e-06) and luminal B (HR = 1.28, p = 0.026).Conclusions: In conclusion, BIRC5 is involved in the development and progression of breast cancer and may be a suitable prognostic marker for human breast cancer.

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Characterizing the Relapse Potential in Different Luminal Subtypes of Breast Cancers with Functional Proteomics

International Journal of Molecular Sciences ◽

10.3390/ijms21176077 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6077

Author(s):

Tung-Yi Lin ◽

Pei-Wen Wang ◽

Chun-Hsun Huang ◽

Pei-Ming Yang ◽

Tai-Long Pan

Keyword(s):

Breast Cancer ◽

Cathepsin D ◽

Treatment Options ◽

Growth Factor Receptor ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Term Survival ◽

Luminal B ◽

Functional Roles ◽

The Matrix

Poor prognosis due to the high relapse and metastasis rates of breast cancer has been particularly linked to the luminal B subtype. The current study utilized MCF-7 and ZR-75-1 to investigate various luminal subtypes of breast cancers that have discrepant expressions in the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). Understanding of the differential protein profiles and the associated pathways could help alleviate the malignance and promote the long-term survival rate of breast cancer patients. Functional proteome tools were applied to comprehensively delineate the global protein alterations that reflect the varieties of biological features between the two subtypes. In this study, a total of 11 proteins with significant and meaningful changes were identified. These protein targets including PRX2, CK19, nucleophosmin and cathepsin D were mostly involved in cell differentiation or proliferation. Particularly, cathepsin D was highly expressed in the luminal B subtype. Moreover, the level of cathepsin-D was also upregulated in the clinical metastatic tissues. Accordingly, the RNA interference-mediated silencing of cathepsin D stimulated ER expression but suppressed the level of HER2. The knockdown of cathepsin D enhanced the level of ZO-1 and a remarkable decrease in N-cadherin was also detected. Again, the matrix metalloproteinases (MMP) activity was impaired under the cathepsin D abolishment. Collectively, this study represented a modality to explore novel relationships in a proteome complex and highlighted the functional roles of cathepsin D in treatment options for different subtypes of breast cancer.

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Glucocorticoid receptors are expressed in diverse molecular subtypes of breast cancer and in peri tumoral stroma: luminal A, luminal B HER+, luminal B HER–, and triple-negative breast cancers

The Breast ◽

10.1016/s0960-9776(19)30147-x ◽

2019 ◽

Vol 44 ◽

pp. S31

Author(s):

F. Buxant ◽

N. Kindt ◽

F. Gubana ◽

X. Catteau ◽

F. Journé ◽

...

Keyword(s):

Breast Cancer ◽

Glucocorticoid Receptors ◽

Triple Negative ◽

Molecular Subtypes ◽

Breast Cancers ◽

Luminal A ◽

Luminal B

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Ki-67 is a Luminal B marker that identifies a high-risk subgroup in hormone receptor positive and node negative breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.10521 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 10521-10521

Author(s):

M. Cheang ◽

D. Voduc ◽

S. Leung ◽

D. Turbin ◽

P. S. Bernard ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Poor Prognosis ◽

Cox Regression ◽

Breast Cancers ◽

Ki 67 ◽

Node Negative ◽

Luminal B ◽

Poor Outcome ◽

Hormone Receptor Positive

10521 Background: Gene expression profiling studies have revealed prognostically significant intrinsic breast cancer subtypes, designated Luminal A, Luminal B, Basal and Her2. Expression of ER and associated genes characterizes the luminal breast cancers. The Lum B subgroup is associated with poor outcome, but we lack immunohistochemical (IHC) markers to distinguish Lum A and Lum B subgroups. MKI67 is one gene known to be highly expressed in Lum B tumors, encoding the Ki-67 protein, a robust marker of cell proliferation. In this study, we perform IHC analysis of Ki-67 in a large breast cancer tissue microarray. Methods: Our patient cohort consists of 2222 consecutive cases of invasive breast cancer referred to the BC Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct a tissue microarray that was then stained for Ki-67 using a commercially available mouse monoclonal antibody. Ki-67 staining was scored quantitatively by automated image analysis and a tumor was positive if the percent positive nuclei was >30%’ Results: Of the 2,222 patients, there are 1,437 Luminal tumors as defined by IHC (ER or PR positive). As Her2 positive status is an established marker of poor prognosis, we excluded these tumors from our analysis. Of the remaining tumors, 9% were Ki-67 positive when using a ki-67 cut off of 30% positive nuclei. In survival analysis of patients ER/PR positive and Her2 negative, we found that Ki-67 identifies a population with poor prognosis (10-yr BCSS 60% vs. 80%). In a multivariate Cox regression we found that Ki-67 is independently prognostic. We repeated Cox regression analysis including only node negative patients and again found that Ki-67 is an independent predictor of poor outcome. Conclusions: Ki-67 has prognostic significance on multivariate survival analysis. Hormone receptor positive and node negative status is typically associated with a favorable outcome for breast cancer. However, Ki-67 is able to identify a small, but clinically significant subgroup with a particularly poor outcome. Defining the Luminal B subtype as (ER or PR) positive and (HER2 or Ki-67) positive, results in a subgroup that contains 18% of hormone receptor positive breast cancers with 10-yr BCSS of 61%. No significant financial relationships to disclose.

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Inmunophenotypic profiles of male breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21180 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21180-21180

Author(s):

T. Martin Gomez ◽

B. Torio ◽

I. Ruiz ◽

F. Arranz ◽

A. Arizcun

Keyword(s):

Breast Cancer ◽

Male Breast Cancer ◽

In Situ Hybridisation ◽

Case Series ◽

Response To Therapy ◽

Male Breast ◽

Breast Cancers ◽

Luminal A ◽

Luminal B ◽

Female Breast

21180 Background: Recently, inmunophenotypic characterization methods have allowed identification of female breast carcinomas into separate groups showing different behaviour and response to therapy: luminal A phenotype (RE +, HER2-neu - ), luminal B (RE +, HER2- neu + ), basal like (RE -, HER2-neu - ). In this study, we used immunohistochemistry to investigate the inmunophenotypic profile distribution of male breast cancer. Methods: all the male breast cancers were obtained from the files of the Departments of Pathology of Hospital Río Carrión in Palencia, Spain, since 1996. A total of 9 cases were reviewed to confirm the diagnosis and to characterize each tumour. The following CK immunohistochemistry was performed: 8/18 and 5 (Dako, Carpinteria, CA, USA) in a Dako autostainer. ER was interpreted as positive if > 10% of the cells were staining. Normal skin and tonsils were used as positive controls for the CK and a known breast cancer for the ER immunohistochemistry. Results: five cases expressed RE and were HER2-neu negative, so they have a luminal-A phenotype. The four cases that expressed the luminal-B pehnotype expressed RE and HER2-neu; we demonstrated gene amplification of the HER-neu gene using fluorescent in situ hybridisation (FISH) in those cases. Respect the CKs profile, all cases were positive for CK 8/18 and negative with CK 5, vimentin and p63, characteristic of luminal-like CK expression profile, according wiht the literature. Conclusions: this is the first case series of male breast cancer patients that provides inmunophenotypic profile data on this rare disease in only one center in Spain. We comunicate that the vast majority of these tumours express the phenotype of luminal-like CKs. None of our patients were basal-like tumours. The percentage expression of Her-2 parallels the finding in female breast cancers and this should be analysed for its predictive significance, according to new specific biological treatments. No significant financial relationships to disclose.

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