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

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.

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ROR1 Potentiates FGFR Signaling in Basal-Like Breast Cancer

Cancers ◽

10.3390/cancers11050718 ◽

2019 ◽

Vol 11 (5) ◽

pp. 718 ◽

Cited By ~ 1

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.

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

10.1101/2020.08.27.269902 ◽

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.

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Effects of Astragalus polysaccharide on proliferation and Akt phosphorylation of the basal-like breast cancer cell line

Journal of Chinese Integrative Medicine ◽

10.3736/jcim20111210 ◽

2011 ◽

Vol 9 (12) ◽

pp. 1339-1346 ◽

Cited By ~ 13

Author(s):

MN Ye

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Breast Cancer Cell Line ◽

Cancer Cell Line ◽

Akt Phosphorylation ◽

Astragalus Polysaccharide ◽

Basal Like Breast Cancer

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Regulation and Action of SKP2 in Cell and Tumor Models: Mechanisms Underlying Aggressive Growth in Basal-Like Breast Cancer

10.21236/ada549245 ◽

2011 ◽

Author(s):

Katerina Fagan-Solis

Keyword(s):

Breast Cancer ◽

Tumor Models ◽

Basal Like Breast Cancer

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miR-205 in Breast Cancer: State of the Art

International Journal of Molecular Sciences ◽

10.3390/ijms22010027 ◽

2020 ◽

Vol 22 (1) ◽

pp. 27

Author(s):

Ilaria Plantamura ◽

Alessandra Cataldo ◽

Giulia Cosentino ◽

Marilena V. Iorio

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Normal Breast ◽

Response To Therapy ◽

Aberrant Expression ◽

Open Questions ◽

Tumor Tissues ◽

Breast Physiology ◽

Cancer Types

Despite its controversial roles in different cancer types, miR-205 has been mainly described as an oncosuppressive microRNA (miRNA), with some contrasting results, in breast cancer. The role of miR-205 in the occurrence or progression of breast cancer has been extensively studied since the first evidence of its aberrant expression in tumor tissues versus normal counterparts. To date, it is known that the expression of miR-205 in the different subtypes of breast cancer is decreasing from the less aggressive subtype, estrogen receptor/progesterone receptor positive breast cancer, to the more aggressive, triple negative breast cancer, influencing metastasis capability, response to therapy and patient survival. In this review, we summarize the most important discoveries that have highlighted the functional role of this miRNA in breast cancer initiation and progression, in stemness maintenance, in the tumor microenvironment, its potential role as a biomarker and its relevance in normal breast physiology—the still open questions. Finally, emerging evidence reveals the role of some lncRNAs in breast cancer progression as sponges of miR-205. Here, we also reviewed the studies in this field.

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