scholarly journals Utilizing the Hippo pathway as a therapeutic target for combating endocrine-resistant breast cancer

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jing Chen ◽  
Runlan Wan ◽  
Qinqin Li ◽  
Zhenghuan Rao ◽  
Yanlin Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Targeted Therapies ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Hippo Pathway ◽  
Endocrine Resistance ◽  
Breast Cancers ◽  
Antitumor Effects ◽  
The Hippo Pathway

AbstractDrug resistance is always a great obstacle in any endocrine therapy of breast cancer. Although the combination of endocrine therapy and targeted therapy has been shown to significantly improve prognosis, refractory endocrine resistance is still common. Dysregulation of the Hippo pathway is often related to the occurrence and the development of many tumors. Targeted therapies of this pathway have played important roles in the study of triple negative breast cancer (TNBC). Targeting the Hippo pathway in combination with chemotherapy or other targeted therapies has been shown to significantly improve specific antitumor effects and reduce cancer antidrug resistance. Further exploration has shown that the Hippo pathway is closely related to endocrine resistance, and it plays a “co-correlation point” role in numerous pathways involving endocrine resistance, including related pathways in breast cancer stem cells (BCSCs). Agents and miRNAs targeting the components of the Hippo pathway are expected to significantly enhance the sensitivity of breast cancer cells to endocrine therapy. This review initially explains the possible mechanism of the Hippo pathway in combating endocrine resistance, and it concludes by recommending endocrine therapy in combination with therapies targeting the Hippo pathway in the study of endocrine-resistant breast cancers.

scholarly journals INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Samuel J. Rodgers ◽  
Lisa M. Ooms ◽  
Viola M. J. Oorschot ◽  
Ralf B. Schittenhelm ◽  
Elizabeth V. Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Akt Signaling ◽  
Late Endosome ◽  
Breast Cancers ◽  
Lysosomal Degradation ◽  
Late Endosomes ◽  
Mrna And Protein Expression

AbstractINPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

scholarly journals Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Lingling Wang ◽  
Jiashen Sun ◽  
Yueyuan Yin ◽  
Yanan Sun ◽  
Jinyi Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Critical Role ◽  
Endocrine Resistance ◽  
Autophagic Flux ◽  
Physical Interaction ◽  
Premature Senescence ◽  
Breast Cancers ◽  
Transcriptional Coregulator

AbstractTo support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.

scholarly journals Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer

2010 ◽  
Vol 28 (18) ◽  
pp. 2966-2973 ◽  
Author(s):  
Marco Colleoni ◽  
Bernard F. Cole ◽  
Giuseppe Viale ◽  
Meredith M. Regan ◽  
Karen N. Price ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Triple Negative ◽  
Alkylating Agents ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Node Negative ◽  
Tumor Subtypes ◽  
Node Negative Breast Cancer

Purpose Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents. Patients and Methods Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present. Results Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease). Conclusion The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.

scholarly journals Targeting the Hippo Pathway for Breast Cancer Therapy

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 422 ◽  
Author(s):  
Liqing Wu ◽  
Xiaolong Yang
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Targeted Therapies ◽  
Hippo Pathway ◽  
Targeted Drugs ◽  
Breast Cancer Therapy ◽  
The World ◽  
Core Components ◽  
Future Direction ◽  
The Hippo Pathway

Breast cancer (BC) is one of the most prominent diseases in the world, and the treatments for BC have many limitations, such as resistance and a lack of reliable biomarkers. Currently the Hippo pathway is emerging as a tumor suppressor pathway with its four core components that regulate downstream transcriptional targets. In this review, we introduce the present targeted therapies of BC, and then discuss the roles of the Hippo pathway in BC. Finally, we summarize the evidence of the small molecule inhibitors that target the Hippo pathway, and then discuss the possibilities and future direction of the Hippo-targeted drugs for BC therapy.

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

scholarly journals Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action

2021 ◽  
Author(s):  
Euphemia Leung ◽  
Petr Tomek ◽  
Moana Tercel ◽  
Johannes Reynisson ◽  
Thomas In Hyeup Park ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Endocrine Therapy ◽  
Mechanism Of Action ◽  
Oestrogen Receptor ◽  
Breast Cancer Cells ◽  
Cytotoxic Effect ◽  
Near Infrared ◽  
Triple Negative ◽  
Mammalian Cell Lines

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with oestrogen receptor positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative as well as oestrogen receptor positive breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells suggesting the mechanism of action differed from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.

scholarly journals The immunomodulatory effects of endocrine therapy in breast cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Huanhuan Huang ◽  
Jun Zhou ◽  
Hailong Chen ◽  
Jiaxin Li ◽  
Chao Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Checkpoint Inhibitors ◽  
Endocrine Resistance ◽  
Tumor Development ◽  
Immune Microenvironment ◽  
Antitumor Effects ◽  
Estrogen Receptor Modulators ◽  
Cancer Multiple

AbstractEndocrine therapies with SERMs (selective estrogen receptor modulators) or SERDs (selective estrogen receptor downregulators) are standard therapies for patients with estrogen receptor (ER)-positive breast cancer. Multiple small molecule inhibitors targeting the PI3K-AKT-mTOR pathway or CDK4/6 have been developed to be used in combination with anti-estrogen drugs to overcome endocrine resistance. In addition to their direct antitumor effects, accumulating evidence has revealed the tumor immune microenvironment (TIM)-modulating effects of these therapeutic strategies, which have not been properly acknowledged previously. The immune microenvironment of breast tumors plays a crucial role in tumor development, metastasis and treatment response to endocrine therapy and immunotherapy. Therefore, in our current work, we comprehensively review the immunomodulatory effect of endocrine therapy and discuss its potential applications in combination with immune checkpoint inhibitors in breast cancer treatment.

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