Abstract 876: Molecular mechanisms of paclitaxel-resistance and resveratrol sensitivity in MDA-MB-231 breast cancer cells.

Down regulation of Pinkbar/pAKT and MMP2/MMP9 expression in MDA-MB-231 breast cancer cells as potential targets in cancer therapy by hAMSCs secretome

Cells Tissues Organs ◽

10.1159/000520370 ◽

2021 ◽

Author(s):

Termeh Shakery ◽

Fatemeh Safari

Keyword(s):

Breast Cancer ◽

Cancer Therapy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Growth Factor Receptor ◽

3D Cell Culture ◽

Therapeutic Effects ◽

Down Regulation ◽

Egfr Signaling Pathway

Breast cancer (BC) is one of the most causes of cancer-related death among women worldwide. Cancer therapy based on stem cells was considered as a novel and promising platform. In present study, we explored the therapeutic effects of human amniotic mesenchymal stromal cells (hAMSCs) through Pinkbar (planar intestinal-and kidney-specific BAR domain protein), pAKT, and matrix metalloproteinases including MMP2, MMP9 on MDA-MB-231 breast cancer cells. To do so, we employed a co-culture system using 6 well plates transwell with a diameter of 0.4 μm pore sized. After 72h hAMSCs-treated MDA-MB-231 breast cancer cells, the expression of Epidermal growth factor receptor (EGFR), and c-Src (a key mediator in EGFR signaling pathway), Pinkbar, pAKT, MMP2, and MMP9 was analyzed by using quantitative real time PCR (qRT-PCR) and western blot methods. Based on using 2D and 3D cell culture models, the significant reduction of tumor cell growth and motility through down regulation of EGFR, c-Src, Pinkbar, pAKT, MMP2, and MMP9 in MDA-MB-231 breast cancer cells was shown. Also, the induction of cellular apoptosis also found. Our finding indicates that the hAMSCS secretome has therapeutic effects on cancer cells. To identify the details of the molecular mechanisms, more experiments will be required.

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IFT20 confers paclitaxel resistance by triggering β-arrestin-1 to modulate ASK1 signaling in breast cancer

10.21203/rs.3.rs-1084134/v1 ◽

2021 ◽

Author(s):

Ni Qiu ◽

Huan Jin ◽

Lulu Cui ◽

Yong-tao Zhan ◽

Hao-ming Xia ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Molecular Mechanism ◽

Breast Cancer Cells ◽

Feedback Inhibition ◽

In Vivo Studies ◽

Paclitaxel Resistance ◽

Western Blots ◽

Paclitaxel Treatment

Abstract Background: System paclitaxel-based chemotherapy is the first-line treatment regimen of defense against breast cancer, but inherent or acquired chemotherapy resistance remains a major obstacle in breast cancer therapy. Elucidating the molecular mechanism of chemoresistance is essential to improve the outcome of patients with breast cancer. Methods: Paclitaxel sensitivity was first evaluated using models of IFT20 deletion and overexpression of breast cancer cells in vitro and in vivo studies to identify the effect of IFT20 on paclitaxel chemoresistance. To delineate the molecular mechanism of IFT20 contributions to paclitaxel chemoresistance, changes in ASK signaling and its downstream JNK cascades expression were quantified using western blots, and the potential involvement of β-arrestin-1 was investigated using co-IP studies. Results: IFT20 is positively associated with shorter relapse-free survival in patients with system paclitaxel-based chemotherapy. High expressed IFT20 in breast cancer cells increases resistance to cell death upon paclitaxel treatment; in contrast, IFT20 knockdown enhances apoptosis in breast cancer cells in response to paclitaxel. Mechanistically, IFT20 triggers β-arrestin-1 to bind with ASK1 and promotes the ubiquitination of ASK1 degradation, leading to attenuating ASK1 signaling and its downstream JNK cascades, which helped cells to escape from cell death during paclitaxel treatment. Conclusion: IFT20 confers to paclitaxel chemoresistance. It interacts with β-arrestin-1 to mediate ubiquitination of ASK1 for feedback inhibition of ASK1/JNK signaling and restrains paclitaxel-induced apoptosis. These findings identify IFT20 as a promising novel target for overcoming paclitaxel resistance in breast cancer.

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Calcineurin regulates the stability and activity of estrogen receptor α

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2114258118 ◽

2021 ◽

Vol 118 (44) ◽

pp. e2114258118

Author(s):

Takahiro Masaki ◽

Makoto Habara ◽

Yuki Sato ◽

Takahiro Goshima ◽

Keisuke Maeda ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Target Genes ◽

Estrogen Receptor Α ◽

The Stability ◽

Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

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ZFHX3 Promotes the Proliferation and Tumor Growth of ER-Positive Breast Cancer Cells Likely by Enhancing Stem-Like Features and MYC and TBX3 Transcription

Cancers ◽

10.3390/cancers12113415 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3415

Author(s):

Ge Dong ◽

Gui Ma ◽

Rui Wu ◽

Jinming Liu ◽

Mingcheng Liu ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Mammary Epithelial Cells ◽

Progesterone Receptors ◽

Mammary Epithelial ◽

Luciferase Reporter ◽

Mammosphere Formation

Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice; and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells’ proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.

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TOPOGRAPHY MEDIATED REGULATION OF HER-2 EXPRESSION IN BREAST CANCER CELLS

Nano LIFE ◽

10.1142/s1793984412410097 ◽

2012 ◽

Vol 02 (03) ◽

pp. 1241009 ◽

Cited By ~ 5

Author(s):

AMITA DAVEREY ◽

AUSTIN C. MYTTY ◽

SRIVATSAN KIDAMBI

Keyword(s):

Breast Cancer ◽

Cell Adhesion ◽

Cancer Cells ◽

Cancer Progression ◽

Breast Tumor ◽

Cancer Biology ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Her 2 ◽

Micro Topography

This article demonstrates that the surface micro-topography regulates the biology of breast cancer cells, including the expression of HER-2 gene and protein. The breast tumor microenvironment is made up of heterogenous mixture of pores, ridges and collagen fibers with well defined topographical features. Although, significant progress has been achieved towards elucidating the biochemical and molecular mechanisms that underlie breast cancer progression, quantitative characterization of the associated mechanical/topographical properties and their role in breast tumor progression remains largely unexplored. Therefore, the aim of this study is to investigate the effect of topography on the adhesion and biology of breast cancer cells in in vitro cultures. Polydimethylsiloxane (PDMS) surfaces containing different topographies were coated with polyelectrolyte multilayers (PEMs) to improve cell adhesion and maintain cell culture. HER-2 expressing breast cancer cells, BT-474 and SKBr3, were cultured on these PDMS surfaces. We demonstrate that micro-topography affects the cell adhesion and distribution depending on the topography on the PDMS surfaces. We also report for the first time that surface topography down-regulates the HER-2 gene transcription and protein expression in breast cancer cells when cultured on PDMS surfaces with micro-topographies compared to the tissue culture polystyrene surface (TCPS) control. Results from this study indicate that micro-topography modulates morphology of cells, their distribution and expression of HER-2 gene and protein in breast cancer cells. This study provides a novel platform for studying the role of native topography in the progression of breast cancer and has immense potential for understanding the breast cancer biology.

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