Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis

The development of new computational approaches that are able to design the correct personalized drugs is the crucial therapeutic issue in cancer research. However, tumor heterogeneity is the main obstacle to developing patient-specific single drugs or combinations of drugs that already exist in clinics. In this study, we developed a computational approach that integrates copy number alteration, gene expression, and a protein interaction network of 73 basal breast cancer samples. 2509 prognostic genes harboring a copy number alteration were identified using survival analysis, and a protein–protein interaction network considering the direct interactions was created. Each patient was described by a specific combination of seven altered hub proteins that fully characterize the 73 basal breast cancer patients. We suggested the optimal combination therapy for each patient considering drug–protein interactions. Our approach is able to confirm well-known cancer related genes and suggest novel potential drug target genes. In conclusion, we presented a new computational approach in breast cancer to deal with the intra-tumor heterogeneity towards personalized cancer therapy.

Download Full-text

Triple negative aggressive phenotype controlled by miR-135b and miR-365: new theranostics candidates

Scientific Reports ◽

10.1038/s41598-021-85746-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gloria Bertoli ◽

Claudia Cava ◽

Fabio Corsi ◽

Francesca Piccotti ◽

Cristina Martelli ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Triple Negative ◽

Differentially Expressed ◽

Tumor Control ◽

Breast Cancers ◽

Basal Breast Cancer ◽

Therapeutic Molecules ◽

Invasive Capacity ◽

Tnbc Subtype

AbstractTriple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.

Download Full-text

Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

Cancers ◽

10.3390/cancers13102318 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2318

Author(s):

Eyyad Nassar ◽

Nourhan Hassan ◽

Eslam A. El-Ghonaimy ◽

Hebatallah Hassan ◽

Mahmoud Salah Abdullah ◽

...

Keyword(s):

Breast Cancer ◽

Tissue Factor ◽

Cell Lines ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Network Formation ◽

Umbilical Vein ◽

Poor Survival ◽

Altered Expression ◽

Basal Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.

Download Full-text

Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

npj Precision Oncology ◽

10.1038/s41698-021-00232-w ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Marilyne Labrie ◽

Allen Li ◽

Allison Creason ◽

Courtney Betts ◽

Jamie Keck ◽

...

Keyword(s):

Breast Cancer ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Patient Specific ◽

Combination Therapies ◽

Breast Cancer Patients ◽

Effector Cells ◽

Basal Breast Cancer ◽

Rational Combination

AbstractIn a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

Download Full-text

Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver

10.1101/479568 ◽

2018 ◽

Cited By ~ 1

Author(s):

Michiel Fokkelman ◽

Esmee Koedoot ◽

Vasiliki-Maria Rogkoti ◽

Sylvia E. Le Dévédec ◽

Iris van de Sandt ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Metastasis ◽

Breast Cancer Cell Lines ◽

Cancer Cell Migration ◽

Metastasis Formation ◽

Breast Cancer Cell Migration ◽

Basal Breast Cancer

AbstractMetastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.

Download Full-text