Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer

Nath, Arijit; Mitra, Sangeeta; Mistry, Tanuma; Pal, Ranita; Nasare, Vilas

doi:10.1007/s12032-021-01610-x

Cited by 19 publications

(10 citation statements)

References 204 publications

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“…In recent years, TNBC was recognized as a heterogeneous group of malignancies, and various molecular and morphological stratification systems have been proposed to reflect its intrinsic variability. At present, molecular and morphological classifications identify TNBCs with distinct biological behaviors resulting in different histopathology, tumor grade and disease progression rate [ 1 , 2 , 3 , 4 , 5 , 6 ]. At variance with other breast tumors, TNBC lacks specific target molecules, and chemotherapy still represents the only effective therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

“…At variance with other breast tumors, TNBC lacks specific target molecules, and chemotherapy still represents the only effective therapeutic strategy. Unfortunately, the drug resistance occurring after the long-term use of chemotherapeutic agents combined with the heterogeneous response to treatments contribute to make this approach ultimately unsuccessful [ 1 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

Grassilli

Brugnoli

Cairo

et al. 2022

JPM

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Triple negative breast cancer (TNBC) represents the most aggressive breast tumor, showing a high intrinsic variability in terms of both histopathological features and response to therapies. Blocking the Akt signaling pathway is a well-studied approach in the treatment of aggressive breast tumors. The high homology among the Akt isoforms and their distinct, and possibly opposite, oncogenic functions made it difficult to develop effective drugs. Here we investigated the role of Vav1 as a potential down-regulator of individual Akt isozymes. We revealed that the over-expression of Vav1 in triple negative MDA-MB-231 cells reduced only the Akt2 isoform, acting at the post-transcriptional level through the up-modulation of miR-29b. The Vav1/miR-29b dependent decrease in Akt2 was correlated with a reduced lung colonization of circulating MDA-MB-231 cells. In cell lines established from PDX, the Vav1 induced down-modulation of Akt2 is strongly dependent on miR-29b and occurs only in some TNBC tumors. These findings may contribute to better classify breast tumors having the triple negative phenotype, and suggest that the activation of the Vav1/miR-29b axis, precisely regulating the amount of an Akt isozyme crucial for tumor dissemination, could have great potential for driving more accurate therapies to TNBCs, often not eligible or resistant to treatments.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

Grassilli

Brugnoli

Cairo

et al. 2022

JPM

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“…The paucity of TNBC therapeutics forces the need for the identification of novel molecular targets along with the devising of additional innovative therapies that will target tumorigenesis and bring plausible rendition to TNBC therapy. 5,[51][52][53][54] Therefore, a few novel approaches have been listed in the following sections that surpass a few of the previous hindrances allowing possible therapy. Some of these novel approaches have undergone several clinical trials, while some are in a preclinical state.…”

Section: Conventional Molecular Targetsmentioning

confidence: 99%

Emerging Futuristic Targeted Therapeutics

Mistry,

Nath,

Pal

et al. 2023

American Journal of Clinical Oncology

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Triple-negative breast cancer is characterized by high lethality attributed to factors such as chemoresistance, transcriptomic, and genomic heterogeneity, leading to a poor prognosis and limiting available targeted treatment options. While the identification of molecular targets remains pivotal for therapy involving chemo drugs, the current challenge lies in the poor response rates, low survival rates, and frequent relapses. Despite various clinical investigations exploring molecular targeted therapies in conjunction with conventional chemo treatment, the outcomes have been less than optimal. The critical need for more effective therapies underscores the urgency to discover potent novel treatments, including molecular and immune targets, as well as emerging strategies. This review provides a comprehensive analysis of conventional treatment approaches and explores emerging molecular and immune-targeted therapeutics, elucidating their mechanisms to address the existing obstacles for a more effective management of triple-negative breast cancer.

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“…Triple-negative breast cancer (TNBC) is hormone receptor (HR)-negative (estrogen receptor (ER)-and progesterone receptor (PR)-negative) and HER2-negative. This type of cancer is more common in women with BRCA1 gene mutations, grows and spreads faster, has limited treatment options, and is associated with poor prognosis (Nath et al, 2021). HER2-enriched breast cancer is HR-negative and HER2-positive.…”

Section: Introductionmentioning

confidence: 99%

Transmembrane 4 L Six Family Member 1 Suppresses Hormone Receptor-–Positive, HER2-Negative Breast Cancer Cell Proliferation

Chen

Zhu

et al. 2022

Front. Pharmacol.

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Background: The prognosis of breast cancer varies according to the molecular subtype. Transmembrane 4 L six family 1 (TM4SF1) exhibits different expression patterns among the molecular subtypes of breast cancer. However, the expression profile of TM4SF1 in hormone receptor HR+HER2- breast cancer remains unclear.Methods: TM4SF1 mRNA levels were examined in major subclasses of breast cancer by analyzing The Cancer Genome Atlas (TCGA) datasets. In addition, TM4SF1 protein and mRNA levels in HR+HER2- breast cancer tissue samples were determined by immunohistochemistry and Western blot assay. The effect of TM4SF1 on cell proliferation was evaluated using MTT, colony formation, 3D organoid, and xenograft models, following the TM4SF1 overexpression or knockdown.Results: TCGA database analysis demonstrated that TM4SF1 was downregulated in breast cancer compared with the healthy adjacent breast tissue. In addition, the expression of TM4SF1 in basal-like one and the mesenchymal TNBC tissue was higher than that of the healthy adjacent breast tissue. Other types, including the luminal androgen receptor–positive TNBC tissue, expressed lower levels of TM4SF1. Immunohistochemistry and real-time quantitative PCR assays demonstrated that the TM4SF1 protein and mRNA levels were downregulated in the HR+HER2- breast cancer tissue compared with the healthy adjacent tissue. Moreover, the TM4SF1 overexpression reduced the viability of MCF-7 and ZR-75-1 breast cancer cells, whilst reducing the number of colonies and 3D-organoids formed by these cell lines. By contrast, TM4SF1 knockdown led to an increased MCF-7 cell proliferation. However, in the TNBC cell line, MDA-MB-231, TM4SF1 silencing reduced cell proliferation. In vivo, the TM4SF1 overexpression inhibited MCF-7 xenograft growth in a nude mouse model, which was associated with the downregulation of the Ki-67 expression, apoptosis induction, and inhibition of the mTOR pathway.Conclusion: TM4SF1 is downregulated in HR + HER2-breast cancer, and the overexpression of TM4SF1 suppresses cell proliferation in this cancer subtype.

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Molecular targets and therapeutics in chemoresistance of triple-negative breast cancer

Cited by 19 publications

References 204 publications

Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

Vav1 Selectively Down-Regulates Akt2 through miR-29b in Certain Breast Tumors with Triple Negative Phenotype

Emerging Futuristic Targeted Therapeutics

Transmembrane 4 L Six Family Member 1 Suppresses Hormone Receptor-–Positive, HER2-Negative Breast Cancer Cell Proliferation

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