Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Conclusions and future direction

    2023-12-16


    Conclusions and future direction ER(−)/PgR(+) breast cancers have a distinct clinical course, response to treatment, and molecular features when compared to other breast cancer types, however some of them are actually technical artifacts or consequences of too high definitions of positivity. According to the current guidelines published by the ASCO/CAP, every case of ER(−)/PgR(+) requires repeated testing with a separate sample [72]. Moreover, we recommend that any such case should be validated by an experienced pathologist, preferentially from a tertiary care center. The biology of ER(−)/PgR(+) breast cancers is probably influenced by sex hormone receptor variants which are not routinely evaluated in clinical practice (e.g. splice variants of ERα, ERβ and AR). Presumably, some miRNAs interfere with transcription and translation of hormone receptor coding genes, thus participating in the pathogenesis of single hormone receptor-positive breast cancers. Hopefully, new therapeutic strategies will emerge, including effective modulation of PgR, AR, and splicing variants of ER, or silencing of miRNA. Thus, further studies concerning the molecular pathogenesis and biology of ER(−)/PgR(+) breast cancer are strongly recommended. Since these cancers respond to both chemotherapy and endocrine therapy, both should be considered in their treatment schedules. Currently, the 2017 St Gallen consensus and the 2017 National Comprehensive Cancer Network guidelines consider the ER(−)/PgR(+) phenotype equivalent to other hormone receptor-positive tumors [2], [73]. Concluding from the above mentioned studies, such approach may be beneficial for some women, although a significant portion of patients may not respond to endocrine treatment. Thus, it may be worthwhile to consider prediction of benefit from endocrine therapy and chemotherapy in ER(−)/PgR(+) cases using gene signatures, especially in “high-risk” patients (intermediate/high tumor burden, high Ki-67, nodal involvement). Since gene signatures are relatively expensive and not generally accessible, Biperiden HCl receptor of surrogate IHC markers (TFF1/CK5/EGFR) proposed by Yu et al. in ER(−)/PgR(+) breast cancer and high tumor grade may potentially designate hormone unresponsive ER(−)/PgR(+) patients [5]. Finally, the institutions which are not routinely performing PgR evaluation should consider this at least in ER(−) tumors to identify patients who can possibly benefit from anti-estrogen treatment.
    Conflict of interest
    Introduction The neurotransmitter acetylcholine (ACh) signals through two types of acetylcholine receptors (AChRs): muscarinic acetylcholine receptors (mAChRs) which are G protein-coupled receptors (GPCRs) and nicotinic acetylcholine receptors which are ligand-gated ion channels. The mAChR family consists of five distinct subtypes named M1 to M5. The M1, M3 and M5 mAChRs couple to G proteins belonging to the Gq/11 family, whereas the other mAChRs (M2 and M4) signal through G proteins of the Gi/o family [1]. From the five different subtypes of mAChR the M1 receptor is most abundantly expressed in the hippocampus, cortex and striatum where they are located at postsynaptic membranes [2]. Activation of M1 receptors leads to the regulation of a range of ion channels that are co-expressed in the same neurons, including the NMDA subtype of glutamate receptors [3], [4], [5] and KCNQ (Kv7) outwardly rectifying potassium channels [6], [7]. Currents through NMDA receptor-coupled ion channels are enhanced upon the activation of muscarinic M1 receptors, whereas currents through KCNQ2/3 potassium channels are reduced in amplitude upon muscarinic M1 receptor activation, both effects resulting in an increase in excitability of the post-synaptic neuron. In patients suffering from Alzheimer's disease cholinergic neurons from the basal forebrain are among the first to undergo severe degeneration [8], [9], resulting in a loss of cholinergic innervation of the hippocampus and the entire cortex. ACh release in the hippocampus has been shown to activate muscarinic M1 receptors resulting in potentiation of currents through NMDA receptors [4]. NMDA receptors play a key role in long-lasting forms of synaptic plasticity, which are the cellular mechanisms underlying learning and memory. Consistent with the above, the activation of muscarinic M1 receptors in the hippocampus has been shown to induce NMDA receptor-dependent long-term potentiation [10]. It has been hypothesized that potentiation of NMDA receptors provides a fundamental mechanism by which cholinergic input to the hippocampus modulates memory and attention. The M1 muscarinic receptor that mediates this potentiation is therefore an attractive target for the development of drugs to treat memory disorders in e.g. Alzheimer's disease [11].