Notch-out for breast cancer therapies

Lamy, M; Ferreira, Andreia; Sales-Dias, Joana; Braga, Sofía; Silva, Gabriela; Barbas, Ana

doi:10.1016/j.nbt.2017.08.004

Cited by 44 publications

(50 citation statements)

References 116 publications

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“…Although mechanisms linking CAF contractility to cancer cell invasion have been described 22,25,64,65 , we unveil here the NOTCH pathway as a key player. NOTCH pathway has been studied in cancer with a strong focus on cancer cells [66][67][68] . Our data show that NOTCH exerts a key role in CAF-S4 contractility and its pro-invasive action in BC.…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

et al. 2020

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Although fibroblast heterogeneity is recognized in primary tumors, both its characterization in and its impact on metastases remain unknown. Here, combining flow cytometry, immunohistochemistry and RNA-sequencing on breast cancer samples, we identify four Cancer-Associated Fibroblast (CAF) subpopulations in metastatic lymph nodes (LN). Two myofibroblastic subsets, CAF-S1 and CAF-S4, accumulate in LN and correlate with cancer cell invasion. By developing functional assays on primary cultures, we demonstrate that these subsets promote metastasis through distinct functions. While CAF-S1 stimulate cancer cell migration and initiate an epithelial-to-mesenchymal transition through CXCL12 and TGFβ pathways, highly contractile CAF-S4 induce cancer cell invasion in 3-dimensions via NOTCH signaling. Patients with high levels of CAFs, particularly CAF-S4, in LN at diagnosis are prone to develop late distant metastases. Our findings suggest that CAF subset accumulation in LN is a prognostic marker, suggesting that CAF subsets could be examined in axillary LN at diagnosis.

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Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

et al. 2020

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“…Additionally, we examined the influence of miR-449a on intracellular Notch signaling. It was observed that Jagged-1, Dll-4, Hes-1 and Hey-1, which are key factors of the canonical Notch pathway and are critical regulators of CRC/CAC metastasis and angiogenesis (27), were all significantly decreased after miR-449a overexpression in SW620 and SW480 cells. However, through the restoration of Notch-1 expression, these effects were partially reversed (Fig.…”

Section: Mir-449a Inhibits Cac Growth and Invasion By Targetingmentioning

confidence: 99%

MicroRNA‑449a is a potential predictor of colitis‑associated colorectal cancer progression

Feng

Song

et al. 2018

Oncol Rep

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An early diagnosis of colitis‑associated colorectal cancer (CAC) is important for its clinical management. However, it is currently difficult to distinguish the different stages of CAC development. MicroRNA dysregulation is common in human colorectal disorders, however little is known regarding whether miRNA affects tumor progression by regulating inflammation. In the present study, we identified a novel miRNA (miR‑449a), the expression of which was significantly reduced in CAC tissues than in paired adjacent non‑cancerous tissues (ANTs). Notably, the level of miR‑449a was in a markedly decreased pattern during the neoplastic transformation of ulcerative colitis (UC)‑to‑CAC, as demonstrated by both clinical investigations and the experimental mouse model induced by AOM/DSS treatment. In addition, we observed that decreased miR‑449a expression was associated with advanced T or N status, later clinical stage and poor histological differentiation of CAC. Mechanistic studies revealed that miR‑449a inhibited the growth and metastasis of human colon cancer cells by directly binding to the 3'‑UTR of Notch‑1 and thereby, suppressed the activation of the Notch signaling pathway. Therefore, these findings provide strong evidence for the translational potential of miR‑449a in the discrimination of patients with UC that is likely to progress into CAC, from those unlikely to progress, as well as in the prognosis and diagnosis of CAC.

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“…12 Recent studies have suggested that PPP is raised in many tumour cells, but maintenance of high hyperplastic in tumour cells through the PPP remains unanswered. 15 It is possible that Nrf2 can adjust the Notch pathway through affecting the PPP and leads to a change in breast cancer cell proliferation and migration, and need to explore its mechanism. Recent studies show that Notch pathway was involved in cell proliferation, differentiation, migration and invasion.…”

mentioning

confidence: 99%

“…14 The synergy of Nrf2 and Notch pathway promotes survival rate of tumour cells, differentiation, invasion and metastasis in the condition of abnormal expression of Nrf2 and Notch pathway. 15 It is possible that Nrf2 can adjust the Notch pathway through affecting the PPP and leads to a change in breast cancer cell proliferation and migration, and need to explore its mechanism.…”

mentioning

confidence: 99%

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Zhang

et al. 2019

J Cellular Molecular Medi

145

100

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Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF‐E2‐related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch‐like ECH‐associated protein 1 (Keap1) reduced the expression of glucose‐6‐phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia‐inducing factor 1α (HIF‐1α) in MCF‐7 and MDA‐MB‐231 cells. Overexpression of Nrf2 up‐regulated the expression of Notch1 via G6PD/HIF‐1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES‐1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2‐driven breast cancer metastasis.

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Notch-out for breast cancer therapies

Cited by 44 publications

References 116 publications

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

MicroRNA‑449a is a potential predictor of colitis‑associated colorectal cancer progression

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

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