The nuclear receptor coactivator 3 also known as NCOA3 is a
protein that, in humans, is encoded by the NCOA3gene.[5][6] NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
Function
NCOA3 is a transcriptional
coactivator protein that contains several
nuclear receptor interacting domains and an intrinsic
histone acetyltransferase activity. NCOA3 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA3, in turn, acylates
histones, which makes downstream DNA more accessible to transcription. Hence, NCOA3 assists
nuclear receptors in the upregulation of gene expression.[7][8]
Several molecular mechanisms implicate NCOA3 (AIB1) in the
endocrine therapy resistance (depicted in the figure). Signaling pathways or mutations (i.e.
HER2/neu overexpression, activating mutations in
PIK3CA (PI3K), activating mutations in the proto-oncogene tyrosine-protein kinase
Src, etc.) that lead to persistent activation of
ERK and/or
PIK3CA/AKT kinase pathways result, in one hand in an enhanced AIB1 transcriptional coactivation capacity,[11] and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression.[12] In both conditions, the equilibrium of estrogen receptor (ER) complex formation is displaced towards a transcriptionally active complex and thus, counteracting the inhibition caused by anti-estrogenic drugs such as
tamoxifen or
fulvestrant (
selective estrogen receptor modulators). The result is the restoration of estrogen-sensitive gene transcription and the promotion of cancer progression and/or relapse.
Notably, tumors diagnosed with concomitant overexpression of AIB1 and
HER2/neu have worse outcome with tamoxifen therapy than all other patients combined.[13] In addition, dormant tumor cells of luminal breast cancers treated with endocrine therapy may acquire with time, mutations that alter kinase signalling pathways and ultimately enhance AIB1 oncogenic functions. Also, estrogen receptor-PAX2 complexes repress HER2/neu expression, but loss of
PAX2 expression may result in de novo HER2/neu expression and initiate endocrine therapy resistance and relapse.[14]
Mechanisms for AIB1-dependent anti-estrogen therapy resistance
Interactions
Nuclear receptor coactivator 3 has been shown to
interact with:
^Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". Am. J. Physiol. Lung Cell Mol. Physiol. 279 (6): L1066-74.
doi:
10.1152/ajplung.2000.279.6.l1066.
PMID11076796.
S2CID27872061.
^Lee WY, Noy N (February 2002). "Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain". Biochemistry. 41 (8): 2500–8.
doi:
10.1021/bi011764+.
PMID11851396.
Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS (1996). "Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer". Cancer Res. 56 (15): 3446–50.
PMID8758910.
Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA (1997). "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet. 100 (1): 114–22.
doi:
10.1007/s004390050476.
PMID9225980.
S2CID25999127.
Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (2000). "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation". J. Cell Sci. 112 (20): 3519–27.
doi:
10.1242/jcs.112.20.3519.
PMID10504300.
The nuclear receptor coactivator 3 also known as NCOA3 is a
protein that, in humans, is encoded by the NCOA3gene.[5][6] NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
Function
NCOA3 is a transcriptional
coactivator protein that contains several
nuclear receptor interacting domains and an intrinsic
histone acetyltransferase activity. NCOA3 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA3, in turn, acylates
histones, which makes downstream DNA more accessible to transcription. Hence, NCOA3 assists
nuclear receptors in the upregulation of gene expression.[7][8]
Several molecular mechanisms implicate NCOA3 (AIB1) in the
endocrine therapy resistance (depicted in the figure). Signaling pathways or mutations (i.e.
HER2/neu overexpression, activating mutations in
PIK3CA (PI3K), activating mutations in the proto-oncogene tyrosine-protein kinase
Src, etc.) that lead to persistent activation of
ERK and/or
PIK3CA/AKT kinase pathways result, in one hand in an enhanced AIB1 transcriptional coactivation capacity,[11] and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression.[12] In both conditions, the equilibrium of estrogen receptor (ER) complex formation is displaced towards a transcriptionally active complex and thus, counteracting the inhibition caused by anti-estrogenic drugs such as
tamoxifen or
fulvestrant (
selective estrogen receptor modulators). The result is the restoration of estrogen-sensitive gene transcription and the promotion of cancer progression and/or relapse.
Notably, tumors diagnosed with concomitant overexpression of AIB1 and
HER2/neu have worse outcome with tamoxifen therapy than all other patients combined.[13] In addition, dormant tumor cells of luminal breast cancers treated with endocrine therapy may acquire with time, mutations that alter kinase signalling pathways and ultimately enhance AIB1 oncogenic functions. Also, estrogen receptor-PAX2 complexes repress HER2/neu expression, but loss of
PAX2 expression may result in de novo HER2/neu expression and initiate endocrine therapy resistance and relapse.[14]
Mechanisms for AIB1-dependent anti-estrogen therapy resistance
Interactions
Nuclear receptor coactivator 3 has been shown to
interact with:
^Naltner A, Wert S, Whitsett JA, Yan C (December 2000). "Temporal/spatial expression of nuclear receptor coactivators in the mouse lung". Am. J. Physiol. Lung Cell Mol. Physiol. 279 (6): L1066-74.
doi:
10.1152/ajplung.2000.279.6.l1066.
PMID11076796.
S2CID27872061.
^Lee WY, Noy N (February 2002). "Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor's ligand binding domain". Biochemistry. 41 (8): 2500–8.
doi:
10.1021/bi011764+.
PMID11851396.
Guan XY, Xu J, Anzick SL, Zhang H, Trent JM, Meltzer PS (1996). "Hybrid selection of transcribed sequences from microdissected DNA: isolation of genes within amplified region at 20q11-q13.2 in breast cancer". Cancer Res. 56 (15): 3446–50.
PMID8758910.
Margolis RL, Abraham MR, Gatchell SB, Li SH, Kidwai AS, Breschel TS, Stine OC, Callahan C, McInnis MG, Ross CA (1997). "cDNAs with long CAG trinucleotide repeats from human brain". Hum. Genet. 100 (1): 114–22.
doi:
10.1007/s004390050476.
PMID9225980.
S2CID25999127.
Ebisawa T, Tada K, Kitajima I, Tojo K, Sampath TK, Kawabata M, Miyazono K, Imamura T (2000). "Characterization of bone morphogenetic protein-6 signaling pathways in osteoblast differentiation". J. Cell Sci. 112 (20): 3519–27.
doi:
10.1242/jcs.112.20.3519.
PMID10504300.