scholarly journals ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 718 ◽  
Author(s):  
Gaurav Pandey ◽  
Nicholas Borcherding ◽  
Ryan Kolb ◽  
Paige Kluz ◽  
Wei Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biochemical Analysis ◽  
Bioinformatics Analysis ◽  
Orphan Receptor ◽  
Potential Therapeutic Target ◽  
Immunodeficient Mice ◽  
Basal Like Breast Cancer ◽  
Cancer Types ◽  
Patient Prognosis ◽  
Aggressive Subtype

Among all breast cancer types, basal-like breast cancer (BLBC) represents an aggressive subtype that lacks targeted therapy. We and others have found that receptor tyrosine kinase-like orphan receptor 1 (ROR1) is overexpressed in BLBC and other types of cancer and that ROR1 is significantly correlated with patient prognosis. In addition, using primary patient-derived xenografts (PDXs) and ROR1-knockout BLBC cells, we found that ROR1+ cells form tumors in immunodeficient mice. We developed an anti-ROR1 immunotoxin and found that targeting ROR1 significantly kills ROR1+ cancer cells and slows down tumor growth in ROR1+ xenografts. Our bioinformatics analysis revealed that ROR1 expression is commonly associated with the activation of FGFR-mediated signaling pathway. Further biochemical analysis confirmed that ROR1 stabilized FGFR expression at the posttranslational level by preventing its degradation. CRISPR/Cas9-mediated ROR1 knockout significantly reduced cancer cell invasion at cellular levels by lowering FGFR protein and consequent inactivation of AKT. Our results identified a novel signaling regulation from ROR1 to FGFR and further confirm that ROR1 is a potential therapeutic target for ROR1+ BLBC cells.

Molecular identification of basal-like breast cancer through genomic analyses across five cancer types.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1011-1011
Author(s):  
Aleix Prat ◽  
Barbara Adamo ◽  
Cheng Fan ◽  
Maria Vidal ◽  
Patricia Galvan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Squamous Cell ◽  
Serous Carcinoma ◽  
Colorectal Cancers ◽  
Ovarian Cancers ◽  
Different Types ◽  
Basal Like Breast Cancer ◽  
Cancer Types ◽  
Tissue Of Origin ◽  
Lung Adenocarcinomas

1011 Background: Common molecular alterations in different types of cancer are being identified and these might be successfully targeted regardless of the tumor´s tissue of origin. To better understand the genomic relationships among different types of cancer, we explored global gene expression patterns across breast, lung, ovarian, brain and colorectal cancers. Methods: A unified set of 1,707 samples of 5 human cancer types (breast [n=547], lung [squamous and adenocarcinomas, n=249], ovarian [serous carcinoma, n=489], brain [glioblastoma multiforme, n=202] and colorectal [n=220]) from The Cancer Genome Atlas (TCGA) project was evaluated. All microarrays were performed at the University of North Carolina under the same protocol and platform. All samples provided in each publication of TCGA were used, except for lung adenocarcinomas where we used TCGA public data. Consensus clustering was used to identify molecular entities, and breast cancer intrinsic subtyping was performed using the PAM50 predictor. Results: A total of 6 distinct and robust molecular entities were identified representing tumors from breast luminal/HER2-enriched, breast Basal-like, lung, ovarian, brain and colorectal cancers. Strikingly, 55%, 26%, 16% of Basal-like breast cancers were found to be more similar to squamous cell lung carcinomas, lung adenocarcinomas and ovarian cancers, respectively, compared to breast luminal/HER2-enriched tumors. Breast cancer intrinsic subtyping identified a Basal-like profile in 55% of squamous cell lung cancers, 53% of ovarian cancers and 8% of lung adenocarcinomas. Finally, single genes and gene signatures tracking cancer-related biological processes such as proliferation, angiogenesis and immune activation were found highly expressed in different proportions across the 6 molecular entities. Conclusions: These data suggest that breast tumors of the Basal-like subtype have a distinct cell of origin compared to luminal/HER2-enriched tumors. Clinical trials focusing on tumors with common profiles and/or biomarker expression rather than their tissue of origin are warranted with a special focus on Basal-like breast cancer, squamous cell lung carcinoma and serous ovarian cancer.

scholarly journals Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

2013 ◽  
Vol 3 (1) ◽  
Author(s):  
Aleix Prat ◽  
Barbara Adamo ◽  
Cheng Fan ◽  
Vicente Peg ◽  
Maria Vidal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Entity ◽  
Genomic Analyses ◽  
Basal Like Breast Cancer ◽  
Cancer Types

Basal-Like Breast Cancer: A Critical Review

2008 ◽  
Vol 26 (15) ◽  
pp. 2568-2581 ◽  
Author(s):  
Emad A. Rakha ◽  
Jorge S. Reis-Filho ◽  
Ian O. Ellis
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Myoepithelial Cells ◽  
Therapeutic Implications ◽  
Basal Like Breast Cancer ◽  
Her 2 ◽  
Triple Negative Phenotype ◽  
Definition Of ◽  
Aggressive Subtype

Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is characterized by an expression signature similar to that of the basal/myoepithelial cells of the breast and is reported to have transcriptomic characteristics similar to those of tumors arising in BRCA1 germline mutation carriers. They are associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 (“triple-negative” phenotype). Therefore, patients with basal-like cancers are unlikely to benefit from currently available targeted systemic therapy. Although basal-like tumors are characterized by distinctive morphologic, genetic, immunophenotypic, and clinical features, neither an accepted consensus on routine clinical identification and definition of this aggressive subtype of breast cancer nor a way of systematically classifying this complex group of tumors has been described. Different definitions are, therefore, likely to produce variable and contradictory results that may hamper consistent identification and development of treatment strategies for these tumors. In this review, we discuss definition, heterogeneity, morphologic spectrum, relation to BRCA1, and clinical significance of this important class of breast cancer.

scholarly journals CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis

2020 ◽  
Author(s):  
Anni Laine ◽  
Srikar G. Nagelli ◽  
Caroline Farrington ◽  
Umar Butt ◽  
Anna N. Cvrljevic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Breast Cancers ◽  
Genetic Profiling ◽  
Checkpoint Signaling ◽  
Damage Response ◽  
Basal Like Breast Cancer ◽  
Cancer Types

AbstractDespite saturated genetic profiling of breast cancers, oncogenic drivers for the clinically challenging basal-like breast cancer (BLBC) subtype are still poorly understood. Here, we demonstrate that CIP2A is selectively essential for DNA damage-induced initiation of mouse BLBC tumors, but not of other cancer types. Mechanistically, CIP2A was discovered genome-widely the closest functional homologue for DNA-damage proteins TopBP1, RHNO, POLQ, NBN and PARP1. CIP2A directly interacts with the ATR-activation domain of TopBP1, and dampens both, chromatin binding of TopBP1 and RAD51, and G2/M checkpoint in DNA-damaged cells. CIP2A also drives BLBC-associated proliferative MYC and E2F1 signaling. Consistently with high DNA-damage response activity BLBCs, and CIP2A’s novel role in checkpoint signaling, CIP2A was found essential for DNA-damaged, and BRCA-mutant BLBC cells. Selective role for CIP2A as BLBC driver was supported by association of high CIP2A expression with poor patient prognosis only in BLBC, but not in other breast cancer types. Therapeutically, small molecule reactivators of PP2A (SMAPs) phenocopy CIP2A-dependent DNA damage response, and inhibit in vivo growth of patient-derived BLBC xenograft. In summary, we discover sub-type selective essential role for CIP2A in BLBC initiation and maintenance that can be explained by its newly discovered association with DNA-damage response, coordinated with regulation of proliferative signaling. The results also identify therapeutic strategy for CIP2A-dependent BLBCs.

scholarly journals MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yubao Wang ◽  
Young-Mi Lee ◽  
Lukas Baitsch ◽  
Alan Huang ◽  
Yi Xiang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Progesterone Receptors ◽  
Luminal Breast Cancer ◽  
Mouse Development ◽  
Basal Like Breast Cancer ◽  
Aggressive Subtype

Despite marked advances in breast cancer therapy, basal-like breast cancer (BBC), an aggressive subtype of breast cancer usually lacking estrogen and progesterone receptors, remains difficult to treat. In this study, we report the identification of MELK as a novel oncogenic kinase from an in vivo tumorigenesis screen using a kinome-wide open reading frames (ORFs) library. Analysis of clinical data reveals a high level of MELK overexpression in BBC, a feature that is largely dependent on FoxM1, a master mitotic transcription factor that is also found to be highly overexpressed in BBC. Ablation of MELK selectively impairs proliferation of basal-like, but not luminal breast cancer cells both in vitro and in vivo. Mechanistically, depletion of MELK in BBC cells induces caspase-dependent cell death, preceded by defective mitosis. Finally, we find that Melk is not required for mouse development and physiology. Together, these data indicate that MELK is a normally non-essential kinase, but is critical for BBC and thus represents a promising selective therapeutic target for the most aggressive subtype of breast cancer.

400 Met as a potential therapeutic target in basal-like breast cancer

2010 ◽  
Vol 8 (5) ◽  
pp. 102
Author(s):  
S. Gastaldi ◽  
A. Bertotti ◽  
F. Galimi ◽  
F. Sassi ◽  
D. Torti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Target ◽  
Potential Therapeutic Target ◽  
Basal Like Breast Cancer

scholarly journals Erratum: Genomic Analyses across Six Cancer Types Identify Basal-like Breast Cancer as a Unique Molecular Entity

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Aleix Prat ◽  
Barbara Adamo ◽  
Cheng Fan ◽  
Vicente Peg ◽  
Maria Vidal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Entity ◽  
Genomic Analyses ◽  
Basal Like Breast Cancer ◽  
Cancer Types

scholarly journals Basal-Like Phenotype in a Breast Carcinoma Case Series from Sudan: Prevalence and Clinical/Pathological Correlations

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Khalid Dafaallah Awadelkarim ◽  
Carmelo Arizzi ◽  
Elgizouli Omer Musa Elamin ◽  
Hussein M. A. Hamad ◽  
Pasquale De Blasio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptors ◽  
Case Series ◽  
Hierarchical Cluster ◽  
Breast Cancers ◽  
Central Sudan ◽  
Younger Age ◽  
Basal Like Breast Cancer ◽  
Her 2 ◽  
Aggressive Subtype

Basal-like breast cancer, an aggressive subtype associated with high grade, poor prognosis, and younger age, is reported frequently in Africa. We analyzed the expression of the basal cytokeratins (CKs) 5/6 and 17 in a case series from Central Sudan and investigated correlations among basal CK status, ER, PgR, and Her-2/neu, and individual/clinicopathological data. Of 113 primary breast cancers 26 (23%), 38 (34%), and 46 (41%) were, respectively, positive for CK5/6, CK17, and combined basal CKs (CK5/6 and/or CK17). Combined basal CK+ status was associated with higher grade (P<.03) and inversely correlated with ER (P<.002), PgR (P=.004) and combined ER and/or PgR (P<.0002). Two clusters based on all tested markers were generated by hierarchical cluster analysis and k-mean clustering: I: designated ``hormone receptors positive/luminal-like’’ and II: designated ``hormone receptors negative’’, including both basal-like and Her-2/neu+ tumors. The most important factors for dataset variance were ER status, followed by PgR, CK17, and CK5/6 statuses. Overall basal CKs were expressed in a fraction of cases comparable to that reported for East and West African case series. Lack of associations with age and tumor size may represent a special feature of basal-like breast cancer in Sudan.

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