Determining Factors in the Therapeutic Success of Checkpoint Immunotherapies against PD-L1 in Breast Cancer: A Focus on Epithelial-Mesenchymal Transition Activation

Breast cancer is the most common neoplasm diagnosed in women around the world. Checkpoint inhibitors, targeting the programmed death receptor-1 or ligand-1 (PD-1/PD-L1) axis, have dramatically changed the outcome of cancer treatment. These therapies have been recently considered as alternatives for treatment of breast cancers, in particular those with the triple-negative phenotype (TNBC). A further understanding of the regulatory mechanisms of PD-L1 expression is required to increase the benefit of PD-L1/PD-1 checkpoint immunotherapy in breast cancer patients. In this review, we will compile the most recent studies evaluating PD-1/PD-L1 checkpoint inhibitors in breast cancer. We review factors that determine the therapeutic success of PD-1/PD-L1 immunotherapies in this pathology. In particular, we focus on pathways that interconnect the epithelial-mesenchymal transition (EMT) with regulation of PD-L1 expression. We also discuss the relationship between cellular metabolic pathways and PD-L1 expression that are involved in the promotion of resistance in TNBC.

Download Full-text

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers

npj Breast Cancer ◽

10.1038/s41523-021-00282-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Leticia De Mattos-Arruda ◽

Javier Cortes ◽

Juan Blanco-Heredia ◽

Daniel G. Tiezzi ◽

Guillermo Villacampa ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Therapy ◽

Epithelial Mesenchymal Transition ◽

Neoadjuvant Treatment ◽

Tumour Microenvironment ◽

Driver Mutations ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Mesenchymal Transition

AbstractThe biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.

Download Full-text

MEST induces epithelial-mesenchymal transition through IL-6/JAK/STAT3 signaling in breast cancers

10.1101/295832 ◽

2018 ◽

Author(s):

Min Soo Kim ◽

Hyun Sook Lee ◽

Yun Jae Kim ◽

Sung Gyun Kang ◽

Do Yup Lee ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Metastasis ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Metastatic Potential ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Promising Target ◽

Twist 1

AbstractThe loss of imprinting of MEST has been linked to certain types of cancer by promoter switching. However, MEST-mediated regulation of tumorigenicity and metastasis are yet to be understood. Herein, we reported that MEST is a key regulator of IL-6/JAK/STAT3/Twist-1 signal pathway-mediated tumor metastasis. Enhanced MEST expression is significantly associated with pathogenesis of breast cancer patients. Also, MEST induces metastatic potential of breast cancer through induction of the EMT-TFs-mediated EMT program. Moreover, MEST leads to Twist-1 induction by STAT3 activation and subsequently enables the induction of activation of the EMT program via the induction of STAT3 nuclear translocation. Furthermore, the c-terminal region of MEST was essential for STAT3 activation via the induction of JAK2/STAT3 complex formation. Finally, MEST significantly increases the breast cancer’s ability to metastasize from the mammary gland to the lung. These observations suggest that MEST is a promising target for intervention to prevent tumor metastasis.

Download Full-text

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Scientific Reports ◽

10.1038/s41598-021-87525-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

L. E. Anselmino ◽

M. V. Baglioni ◽

F. Malizia ◽

N. Cesatti Laluce ◽

C. Borini Etichetti ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Drug Repositioning ◽

Combined Treatment ◽

Alternative Therapy ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Tumor Types

AbstractDrug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

Download Full-text

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

Nature Communications ◽

10.1038/s41467-020-20173-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Jia-Wern Pan ◽

Muhammad Mamduh Ahmad Zabidi ◽

Pei-Sze Ng ◽

Mei-Yee Meng ◽

Siti Norhidayu Hasan ◽

...

Keyword(s):

Breast Cancer ◽

Somatic Mutations ◽

Checkpoint Inhibitors ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Breast Tumours ◽

Different Populations ◽

Caucasian Women ◽

Molecular Landscape ◽

Immune Score

AbstractMolecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

Download Full-text

Twist-mediated PAR1 induction is required for breast cancer progression and metastasis by inhibiting Hippo pathway

Cell Death and Disease ◽

10.1038/s41419-020-2725-4 ◽

2020 ◽

Vol 11 (7) ◽

Author(s):

Yifan Wang ◽

Ruocen Liao ◽

Xingyu Chen ◽

Xuhua Ying ◽

Guanping Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Invasive Breast Cancer ◽

Breast Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Hippo Pathway ◽

Breast Cancer Patients ◽

Mesenchymal Transition

Abstract Breast cancer is considered to be the most prevalent cancer in women worldwide, and metastasis is the primary cause of death. Protease-activated receptor 1 (PAR1) is a GPCR family member involved in the invasive and metastatic processes of cancer cells. However, the functions and underlying mechanisms of PAR1 in breast cancer remain unclear. In this study, we found that PAR1 is highly expressed in high invasive breast cancer cells, and predicts poor prognosis in ER-negative and high-grade breast cancer patients. Mechanistically, Twist transcriptionally induces PAR1 expression, leading to inhibition of Hippo pathway and activation of YAP/TAZ; Inhibition of PAR1 suppresses YAP/TAZ-induced epithelial-mesenchymal transition (EMT), invasion, migration, cancer stem cell (CSC)-like properties, tumor growth and metastasis of breast cancer cells in vitro and in vivo. These findings suggest that PAR1 acts as a direct transcriptionally target of Twist, can promote EMT, tumorigenicity and metastasis by controlling the Hippo pathway; this may lead to a potential therapeutic target for treating invasive breast cancer.

Download Full-text

Pathways to Breast Cancer Recurrence

ISRN Oncology ◽

10.1155/2013/290568 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 27

Author(s):

Aamir Ahmad

Keyword(s):

Breast Cancer ◽

Epithelial Mesenchymal Transition ◽

Recurrent Disease ◽

Current Knowledge ◽

Cancer Recurrence ◽

Breast Cancer Recurrence ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Number Of Factors ◽

Prevention Of Breast Cancer

Breast cancer remains a deadly disease, even with all the recent technological advancements. Early intervention has made an impact, but an overwhelmingly large number of breast cancer patients still live under the fear of “recurrent” disease. Breast cancer recurrence is clinically a huge problem and one that is largely not well understood. Over the years, a number of factors have been studied with an overarching aim of being able to prognose recurrent disease. This paper attempts to provide an overview of our current knowledge of breast cancer recurrence and its associated challenges. Through a survey of the literature on cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), various signaling pathways such as Notch/Wnt/hedgehog, and microRNAs (miRNAs), we also examine the hypotheses that are currently under investigation for the prevention of breast cancer recurrence.

Download Full-text

Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells

Cancers ◽

10.3390/cancers12092482 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2482

Author(s):

Samson Mathews Samuel ◽

Elizabeth Varghese ◽

Lenka Koklesová ◽

Alena Líšková ◽

Peter Kubatka ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Acquired Resistance ◽

Breast Cancers ◽

Intrinsic Resistance ◽

Mesenchymal Transition ◽

Cancer Breast

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.

Download Full-text

Checkpoint Inhibitors in Breast Cancer - Current Status and Future Directions

Breast Care ◽

10.1159/000486706 ◽

2018 ◽

Vol 13 (1) ◽

pp. 27-31 ◽

Cited By ~ 4

Author(s):

Joachim Bischoff

Keyword(s):

Breast Cancer ◽

T Cell Activation ◽

Cell Activation ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Death Receptor ◽

Target Population ◽

Current Status ◽

Immune Checkpoints ◽

Breast Cancer Patients

Antineoplastic agents directly targeting tumor cells have represented the major strategy of systemic anticancer therapy for many years. Nevertheless, overcoming resistance mechanisms remains a great challenge because treatment options are limited in many cases. From this point of view, immunotherapeutic approaches seem promising in a broad spectrum of solid tumors. These include in particular the currently available inhibitors directed against immune checkpoints leading to a significant T-cell activation. To date, the programmed death receptor 1 (PD-1) and its ligand are the most prominent targets in this context. However, the role of checkpoint inhibitors in the treatment of breast cancer is still being debated, and the main focus is on triple-negative breast cancer patients as a target population in many ongoing trials. Moreover, the potential superiority of combinations with other anticancer drugs such as cytotoxics and targeted agents will be discussed.

Download Full-text