Molecule Information

General Information of the Molecule (ID: Mol04407)

• Name: Nuclear receptor subfamily 6 group A member 1 (NR6A1) ,Homo sapiens
• Synonyms: Germ cell nuclear factor ; Retinoid receptor-related testis-specific receptor
• Molecule Type: Protein
• Gene Name: NR6A1
• Gene ID: 2649
• Sequence:
  MERDEPPPSGGGGGGGSAGFLEPPAALPPPPRNGFCQDELAELDPGTISVSDDRAEQRTC
  LICGDRATGLHYGIISCEGCKGFFKRSICNKRVYRCSRDKNCVMSRKQRNRCQYCRLLK
  C LQMGMNRKAIREDGMPGGRNKSIGPVQISEEEIERIMSGQEFEEEANHWSNHGDSDHS
  SP GNRASESNQPSPGSTLSSSRSVELNGFMAFREQYMGMSVPPHYQYIPHLFSYSGHSP
  LLP QQARSLDPQSYSLIHQLLSAEDLEPLGTPMLIEDGYAVTQAELFALLCRLADELLF
  RQIA WIKKLPFFCELSIKDYTCLLSSTWQELILLSSLTVYSKQIFGELADVTAKYSPSD
  EELHR FSDEGMEVIERLIYLYHKFHQLKVSNEEYACMKAINFLNQDIRGLTSASQLEQL
  NKRYWY ICQDFTEYKYTHQPNRFPDLMMCLPEIRYIAGKMVNVPLEQLPLLFKVVLHSC
  KTSVGKE
• Function: Orphan nuclear receptor that binds to a response elementcontaining the sequence 5'-TCAAGGTCA-3' . Acts as aregulator of embryonic stem cell pluripotency by mediating repressionof POU5F1/OCT4: binds to the DR0 element within the POU5F1/OCT4promoter and inhibits POU5F1/OCT4 expression during embryonic stem celldifferentiation . Involved in the regulation of geneexpression in germ cell development during gametogenesis . {ECO:0000250|UniProtKB:Q64249,ECO:0000269|PubMed:26769970}.
• Uniprot ID: NR6A1_HUMAN
• Ensembl ID: ENSG0000014820017
• HGNC ID: HGNC:7985

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Sirolimus

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Sirolimus
• Molecule Alteration: Epigenetic modification; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Immunoblotting assay assay
• Mechanism Description: Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Sirolimus
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NR6A1/DNMT3A signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Immunoblotting assay assay
• Mechanism Description: Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Sirolimus
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNMT3A signaling pathway; Regulation; N.A.
• In Vitro Model: MCF-7/Rap cells; Breast; Homo sapiens (Human); N.A.
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation.

Tamoxifen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Epigenetic modification; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Immunoblotting assay assay
• Mechanism Description: Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NR6A1/DNMT3A signaling pathway; Regulation; N.A.
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Immunoblotting assay assay
• Mechanism Description: Resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A.Suppresses ERalpha activity, induces partial resistance to rapamycin and tamoxifen, and slightly decreases DNMT3A expression, indicating a functional interplay between NR6A1 and DNMT3A signaling. The development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes.

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNMT3A signaling pathway; Regulation; N.A.
• In Vitro Model: MCF-7/T cells; Breast; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation.

Disease Class: Breast adenocarcinoma [ICD-11: 2C60.1] [1]

• Resistant Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Resistant Drug: Tamoxifen
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: DNMT3A signaling pathway; Regulation; N.A.
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation.

References

• Ref 1: Breast cancer cell resistance to hormonal and targeted therapeutics is correlated with the inactivation of the NR6A1 axis. Cancer Drug Resist. 2024 Nov 23;7:48.