Two Faces of TGF-Beta1 in Breast Cancer

Breast cancer (BC) is potentially life-threatening malignancy that still causes high mortality among women. Scientific research in this field is focused on deeper understanding of pathogenesis and progressing of BC, in order to develop relevant diagnosis and improve therapeutic treatment. Multifunctional cytokine TGF-β1 is one of many factors that have a direct influence on BC pathophysiology. Expression of TGF-β1, induction of canonical and noncanonical signaling pathways, and mutations in genes encoding TGF-β1 and its receptors are correlated with oncogenic activity of this cytokine. In early stages of BC this cytokine inhibits epithelial cell cycle progression and promotes apoptosis, showing tumor suppressive effects. However, in late stages, TGF-β1 is linked with increased tumor progression, higher cell motility, cancer invasiveness, and metastasis. It is also involved in cancer microenvironment modification and promotion of epithelial to mesenchymal transition (EMT). This review summarizes the current knowledge on the phenomenon called “TGF-β1 paradox”, showing that better understanding of TGF-β1 functions can be a step towards development of new therapeutic approaches. According to current knowledge several drugs against TGF-β1 have been developed and are either in nonclinical or in early stages of clinical investigation.

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Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells

Journal of Clinical Medicine ◽

10.3390/jcm8050642 ◽

2019 ◽

Vol 8 (5) ◽

pp. 642 ◽

Cited By ~ 12

Author(s):

Snahlata Singh ◽

Rumela Chakrabarti

Keyword(s):

Breast Cancer ◽

Tumor Progression ◽

Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Therapeutic Response ◽

Current Knowledge ◽

Cell Contact ◽

Invasive Potential ◽

Mesenchymal Transition ◽

Tumor Growth And Metastasis

Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression and metastatic invasion. In breast cancer, EMT both increases the migratory capacity and invasive potential of tumor cells, and initiates protumorigenic alterations in the tumor microenvironment (TME). In particular, recent evidence has linked increased expression of EMT markers such as TWIST1 and MMPs in breast tumors with increased immune infiltration in the TME. These immune cells then provide cues that promote immune evasion by tumor cells, which is associated with enhanced tumor progression and metastasis. In the current review, we will summarize the current knowledge of the role of EMT in the biology of different subtypes of breast cancer. We will further explore the correlation between genetic switches leading to EMT and EMT-induced alterations within the TME that drive tumor growth and metastasis, as well as their possible effect on therapeutic response in breast cancer.

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Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways

Pharmaceuticals ◽

10.3390/ph14111122 ◽

2021 ◽

Vol 14 (11) ◽

pp. 1122

Author(s):

Michelle M. Williams ◽

Sabrina A. Hafeez ◽

Jessica L. Christenson ◽

Kathleen I. O’Neill ◽

Nia G. Hammond ◽

...

Keyword(s):

Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Checkpoint Inhibitors ◽

Clinical Investigation ◽

Cell Metabolism ◽

Breast Cancer Subtype ◽

Primary Tumors ◽

Mesenchymal Transition ◽

Response To Chemotherapy ◽

Metastatic Sites

Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.

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The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666191220142741 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1787-1796

Author(s):

Agata Binienda ◽

Sylwia Ziolkowska ◽

Elzbieta Pluciennik

Keyword(s):

Breast Cancer ◽

Therapeutic Strategy ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Mesenchymal Transition ◽

Anticancer Properties ◽

Main Component ◽

Inhibit Cell Proliferation ◽

Inflammatory Effect

Background: Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas. Methods: his review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway. Results: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma. Conclusion: Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.

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Standard of Care and Promising New Agents for the Treatment of Mesenchymal Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers13051080 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1080

Author(s):

Silvia Mezi ◽

Andrea Botticelli ◽

Giulia Pomati ◽

Bruna Cerbelli ◽

Simone Scagnoli ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Epithelial To Mesenchymal Transition ◽

Triple Negative ◽

Current Knowledge ◽

Standard Of Care ◽

Transition Process ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Expression Of Genes

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mesenchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients.

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Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽

10.3390/molecules26113143 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3143

Author(s):

Sergey E. Parfenyev ◽

Sergey V. Shabelnikov ◽

Danila Y. Pozdnyakov ◽

Olga O. Gnedina ◽

Leonid S. Adonin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Malignant Neoplasm ◽

Malignant Neoplasms ◽

Breast Cancer Patients ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

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Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Cancers ◽

10.3390/cancers13020259 ◽

2021 ◽

Vol 13 (2) ◽

pp. 259

Author(s):

Monish Ram Makena ◽

Myungjun Ko ◽

Donna Kimberly Dang ◽

Rajini Rao

Keyword(s):

Breast Cancer ◽

Secretory Pathway ◽

Histone Deacetylase Inhibitors ◽

Epithelial To Mesenchymal Transition ◽

Molecular Subtype ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Tumor Cell Migration ◽

Canonical Wnt

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

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miRNA proxy approach reveals hidden functions of glycosylation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1502076112 ◽

2015 ◽

Vol 112 (23) ◽

pp. 7327-7332 ◽

Cited By ~ 21

Author(s):

Tomasz Kurcon ◽

Zhongyin Liu ◽

Anika V. Paradkar ◽

Christopher A. Vaiana ◽

Sujeethraj Koppolu ◽

...

Keyword(s):

Posttranslational Modification ◽

Epithelial To Mesenchymal Transition ◽

Biological Function ◽

Regulatory Elements ◽

Rapid Identification ◽

Mesenchymal Transition ◽

Disease States ◽

Mesenchymal To Epithelial Transition ◽

Genes Encoding ◽

Target Network

Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase (B3GLCT), beta-galactoside alpha-2,3-sialyltransferase 5 (ST3GAL5), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-β–induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states.

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