Nuclear Mechanisms Involved in Endocrine Resistance

Dittmer, Jürgen

doi:10.3389/fonc.2021.736597

Cited by 11 publications

(11 citation statements)

References 258 publications

(336 reference statements)

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“…And one resistance mechanism upstream of the signaling pathways and growth factor receptors is increased expression of receptor ligands, such as heregulin [24,25,28]. In our studies we also observed the inactivation of STAT3 and STAT5, and enhanced STAT3 signaling has been linked to the development of estrogen resistance [26]. Collectively, our data demonstrate that GZ17-6.02 and palbociclib interact through multiple individual mechanisms to reduce cell viability.…”

Section: Discussionsupporting

confidence: 66%

“…Loss of ER function will play a role reduced growth and in reduced viability [19]. ER+ mammary carcinoma cells have been shown to develop resistance to direct ER inhibitors through several mechanisms, most notably through activation of PI3K-AKT and MEK1/2-ERK1/2 signaling [22][23][24][25][26][27][28][29]. And one resistance mechanism upstream of the signaling pathways and growth factor receptors is increased expression of receptor ligands, such as heregulin [24,25,28].…”

Section: Discussionmentioning

confidence: 99%

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GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

et al. 2022

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GZ17-6.02 is presently undergoing clinical evaluation in solid tumors and lymphoma. The present studies were performed to define its biology in estrogen receptor positive breast cancer cells and to determine whether it interacted with palbociclib to enhance tumor cell killing. GZ17-6.02 interacted in an additive fashion with palbociclib to kill ER+ breast cancer cells. GZ17-6.02 and palbociclib cooperated to inactivate mTOR and AKT and to activate ULK1 and PERK. The drugs interacted to increase the expression of FAS-L and BAX, and to decrease the levels of MCL1, the estrogen receptor, and HDACs 1-3. Palbociclib activated ERBB3, an effect blocked by GZ17-6.02. GZ17-6.02 and palbociclib interacted to increase the expression of multiple toxic BH3 domain proteins and to reduce MCL1 and BCL-XL expression. Knock down of FAS-L reduced the lethality of [GZ17-6.02 + palbociclib]. GZ17-6.02 and palbociclib interacted to enhance autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5, BAG3, eIF2α, toxic BH3 domain proteins or CD95 significantly reduced drug combination lethality. GZ17-6.02 and palbociclib increased the expression of Beclin1 and ATG5, effects blocked by knock down of eIF2α. The drugs also increased the phosphorylation of the AMPK and ATG13, effects blocked by knock down of ATM. Knock down of ATM or the AMPK, or expression of activated mTOR significantly reduced the abilities of GZ17-6.02 and palbociclib to enhance autophagosome formation and autophagic flux.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

et al. 2022

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“…Such phosphorylations can be triggered by receptor tyrosine kinases (RTKs) through the PI3K/AKT/mTOR/p70S6K and the Ras/Raf/MEK1/ERK1/2 pathways. Endocrine resistance, the resistance to endocrine therapy, is often caused by permanent activation of RTKs ( 35 – 37 ). Of the RTKs, IGF1R is of particular importance for ERα-dependent transcription.…”

Section: Estrogen Receptor αmentioning

confidence: 99%

Biological effects and regulation of IGFBP5 in breast cancer

Dittmer

2022

Front. Endocrinol.

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The insulin-like growth factor receptor (IGF1R) pathway plays an important role in cancer progression. In breast cancer, the IGF1R pathway is linked to estrogen-dependent signaling. Regulation of IGF1R activity is complex and involves the actions of its ligands IGF1 and IGF2 and those of IGF-binding proteins (IGFBPs). Six IGFBPs are known that share the ability to form complexes with the IGFs, by which they control the bioavailability of these ligands. Besides, each of the IGFBPs have specific features. In this review, the focus lies on the biological effects and regulation of IGFBP5 in breast cancer. In breast cancer, estrogen is a critical regulator of IGFBP5 transcription. It exerts its effect through an intergenic enhancer loop that is part of the chromosomal breast cancer susceptibility region 2q35. The biological effects of IGFBP5 depend upon the cellular context. By inhibiting or promoting IGF1R signaling, IGFBP5 can either act as a tumor suppressor or promoter. Additionally, IGFBP5 possesses IGF-independent activities, which contribute to the complexity by which IGFBP5 interferes with cancer cell behavior.

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“…In recent years, many new classes of antitumour compounds with a significant effect on the signalling pathways in tumour cells have been developed [1][2][3][4][5][6]. Along with the new classes, antihormonal drugs-SERMs (selective oestrogen receptor modulators) and SERDs (selective oestrogen receptor degraders)-remain highly relevant as an antitumour therapy [7][8][9]. Hormone therapy [10][11][12][13][14] is one of the most common types of treatment of hormone-dependent tumours including breast cancer, ovarian cancer, endometrial and prostate tumours.…”

Section: Introductionmentioning

confidence: 99%

“…Ten years of tamoxifen treatment reduced the incidence of breast cancer recurrence by more than 25%, compared with 5 years of tamoxifen treatment [24]. Despite the high effectiveness of tamoxifen, the problem of resistance to this drug is especially urgent [7,[25][26][27].…”

Section: Introductionmentioning

confidence: 99%

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance

et al. 2021

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Hormone therapy is one of the most effective breast cancer treatments, however, its application is limited by the progression of hormonal resistance, both primary or acquired. The development of hormonal resistance is caused either by an irreversible block of hormonal signalling (suppression of the activity or synthesis of hormone receptors), or by activation of oestrogen-independent signalling pathways. Recently the effect of exosome-mediated intercellular transfer of hormonal resistance was revealed, however, the molecular mechanism of this effect is still unknown. Here, the role of exosomal miRNAs (microRNAs) in the transferring of hormonal resistance in breast cancer cells has been studied. The methods used in the work include extraction, purification and RNAseq of miRNAs, transfection of miRNA mimetics, immunoblotting, reporter analysis and the MTT test. Using MCF7 breast cancer cells and MCF7/T tamoxifen-resistant sub-line, we have found that some miRNAs, suppressors of oestrogen receptor signalling, are overexpressed in the exosomes of the resistant breast cancer cells. The multiple (but not single) transfection of one of the identified miRNA, miR-181a-2, into oestrogen-dependent MCF7 cells induced the irreversible tamoxifen resistance associated with the continuous block of the oestrogen receptor signalling and the activation of PI3K/Akt pathway. We suppose that the miRNAs-ERα suppressors may act as trigger agents inducing the block of oestrogen receptor signalling and breast cancer cell transition to an aggressive oestrogen-independent state.

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Nuclear Mechanisms Involved in Endocrine Resistance

Cited by 11 publications

References 258 publications

GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

GZ17-6.02 and palbociclib interact to kill ER+ breast cancer cells

Biological effects and regulation of IGFBP5 in breast cancer

Towards Unravelling the Role of ERα-Targeting miRNAs in the Exosome-Mediated Transferring of the Hormone Resistance

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