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Gene Section
Review
BCAR1 (breast cancer anti-estrogen resistance 1)
Allison Berrier
Department of Oral and Craniofacial Biology, LSUHSC-NO School of Dentistry, 1100 Florida Avenue,
Clinical Bldg, Room 8301, New Orleans, LA 70119, USA (AB)
Published in Atlas Database: December 2011
Online updated version : http://AtlasGeneticsOncology.org/Genes/BCAR1ID761ch16q23.html
DOI: 10.4267/2042/47321
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Other names: CAS, CAS1,
FLJ12176, FLJ45059, P130Cas
HGNC (Hugo): BCAR1
Location: 16q23.1
DNA/RNA
CASS1,
CRKAS,
See figure 1 below.
Figure 1.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5)
329
BCAR1 (breast cancer anti-estrogen resistance 1)
Berrier A
3 domain (SH3) domain that binds proline-rich PxxP
ligands. The adjacent region 66-447 aa contains the
substrate domain (SD) comprised of 15 YxxP motifs
that when phosphorylated by tyrosine kinases provides
canonical binding sites for proteins containing SH2
domains such as Crk, mechanical forces and stretching
of SD may induce conformational changes that allows
phosphorylation by kinases and this stretching may
promote protein-protein interactions in this domain
(Sawada et al., 2006). The serine rich domain within
448-610 aa (serine rich protein interaction domain)
contains a four-helix bundle that functions as a scaffold
for BCAR1 binding proteins such as Grb2 and 14-3-3
(Nasertorabi et al., 2004; Briknarová et al., 2005). The
C-terminal domain of 746-870 aa has a potential FAT
(focal adhesion targeting) domain and a helix-loophelix domain with homology to the transcription factor
Id.
This region contains the YDYVHL motif that is
phosphorylated during cell adhesion.
BCAR1 interacting proteins (BioGRID)
CRKII, p60-Src, PTPN12, PTK2 (FAK), RapGEF1
(C3G), NPHP1, PTPN1 (PTP1B), FES, SHIP2
(INPPL1), ARHGAP32 (p250GAP), Pyk2 (PTK2B),
Fyn, CRKL, YWHAZ, SrcIN1 (SNIP), p85-alpha
(PI3KR1), c-ABL (bcr/abl), Lyn, Grb2, Dock1,
paxillin, TRIP6, SH-PTP2, ID2A, UHRF2, NEDD9,
NCK1, VCL, SAP1, Zyxin, BCAR3 (AND-34),
CD2AP, LCK, SFN, SH2D3C, JNK/SAPK1,
SH3KBP1, tensin 1 (TNS1), HCK, EFS, E2F2, VPS11,
HspA5, TUBA1A, GADD34, p140Cap, BCAR1
(p130CAS), PTP-PEST, CIZ, Aurora-A, 14-3-3,
CHAT-H, AIP4, APC/C and CDH1.
Protein
Note
BCAR1 isoforms
Isoform 1: 916 aa, calc MW= 97,7 kDa. Isoform 2: 888
aa, (alternate 5' sequence compared to variant 1) calc
MW= 95,1 kDa. Isoform 3: 888 aa, (alternate 5'
sequence compared to variant 1) calc MW= 95,3 kDa.
Isoform 4: 888 aa, (alternate 5' sequence and alternate
splice site in the substrate domain compared to variant
1 resulting in a different N-terminus and additional
segment in the middle region compared to isoform 1)
calc MW= 95,3 kDa. Isoform 5: 870 aa, (lacks an exon
in the 5' region, alternate AUG start codon, has a
different N-terminus compared to isoform 1) calc
MW= 93,16 kDa. Isoform 6: 870 aa, (different Nterminus compared to isoform 1) calc MW= 93,2 kDa.
Isoform 7, 868 aa (shorter, alternate 5' sequence,
different N-terminus compared to isoform 1) calc
MW= 93 kDa. Isoform 8, 722 aa, (alternate internal
sequence compared to isoform 1, different N-terminus
compared to isoform 1) calc MW= 77,6 kDa. Isoform
9: 660 aa, (shorter alternate 5' sequence, different Nterminus compared to isoform 1) calc MW= 70,7 kDa.
BCAR
proteins
migrate
during
SDS-PAGE
electrophoresis at a significantly higher molecular
weight than predicted from sequence analysis perhaps
due to the extensive phosphorylation of BCAR
proteins. Calculated MW 93,2 kDa, SDS-PAGE
observed MW 130 kDa. Potential sites of human
BCAR1 phosphorylation (PhosphoSitePlus): tyrosine
residues aa 12, 128, 165, 192, 222, 224, 234, 249, 267,
287, 306, 327, 362, 372, 387, 410, 653, 664, 666;
serine residues aa 134, 139, 292, 437, 639; and
threonine residues aa 269, 326, 385. Inducers of
BCAR1 phosphorylation include cell matrix adhesion,
extracellular matrix rigidity, growth factors, hormones
and progression through the cell cycle. Phosphorylation
of BCAR1 regulates BCAR1 dependent activities
through altering protein interactions, protein
localization and signaling cascades (Tikhmyanova et
al., 2010).
Expression
BCAR1 is ubiquitously expressed and is reportedly
detectable in all phases of the cell cycle. In lymphoid
development, BCAR is expressed at higher levels in
differentiated cells compared to precursors. Barrett's
esophagus cancer cell line compared to normal tissue
2,51 increase in BCAR1 expression (Oncomine).
Colorectal cancer Ramaswamy multi-cancer there is a
4,2 fold increase in BCAR1 expression compared to
other cancers (Oncomine). Gastric cancer cell line
Gyorffy cell line 2 there is a 5,0 fold reduction in
BCAR 1 expression (Oncomine). In lymphomas,
BCAR1 expression is reduced 2,5 fold (Oncomine).
Description
BCAR1 domains as described in Tikhmyanova et al.,
2010 are shown in the schematic diagram in figure 2.
The amino terminal 1-65 aa contain the Src homology
Figure 2. Schematic diagram containing BCAR1 protein domains.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5)
330
BCAR1 (breast cancer anti-estrogen resistance 1)
Berrier A
It was also identified as a protein that is tyrosine
phosphorylated after clustering integrin β1 in Tlymphocytes. NEDD9 (neural precursor cell expressed,
developmentally down-regulated 9) is a gene restricted
in expression to early embryonic, but not adult mouse
brain.
The fourth family member is CASS4 ((HEF-EFSP130CAS-like)/CAS4) that maps to chromosome
20q13.2-q13.31 and is the newest member of the family
that was identified by genomic and transcript homology
and demonstrated to function similarly to other BCAR
family members.
These 4 proteins are conserved from jawed vertebrates
through mammals. One BCAR member is found in
lower vertebrates and insects.
However, no BCAR family member is detectable in C.
elegans, S. cerevisiae and other lower eukaryotes.
Localisation
Cytoplasm, ruffles, cell junctions (Donaldson et al.,
2000), nucleus (Kim et al., 2004) and focal adhesions
(Nakamoto et al., 1997; Volberg et al., 1995;
Winograd-Katz et al., 2009).
Function
BCAR1 regulates numerous cellular processes such as
invasion, migration, transformation, survival and drug
resistance (Di Stefano et al., 2011; Brábek et al., 2004;
Brábek et al., 2005) (summarized in figure 3). BCAR1
lacks intrinsic enzymatic activity, yet it is a substrate
for several kinases including the Src tyrosine kinase.
The original name for BCAR1 was p130CAS
abbreviated from Crk-associated substrate because it
was first identified as a tyrosine phosphorylated protein
in cells transformed by v-src and v-crk oncogenes.
BCAR1 regulates cellular behavior by controlling
signaling cascades and the dynamic localization of
multi-protein complexes. The BCAR1 phosphorylation
state is regulated during the cell cycle. During the exit
of G2, BCAR1 serine and threonine phosphorylation
levels increase and these events disrupt the interactions
of BCAR1 with Src and FAK and thus dissociates this
complex and contributes to the disassembly of focal
adhesions allowing cells to loosen matrix adhesions
and thus permitting cell rounding in mitosis. The
subsequent reformation of matrix adhesions promotes
progression through the cell cycle from mitosis to G1
(Pugacheva et al., 2006).
Mutations
Somatic
Catalogue of somatic mutations in cancer: there are
currently 10 known somatic mutations in BCAR1.
Proceeding from the N-terminus to the C-Terminus of
BCAR1, aa 118 proline (identified in the central
nervous system), 185 alanine (identified in the central
nervous system), 407 threonine (identified in breast
tissue), 430 serine (upper aerodigestive tract), 583
serine (identified in prostate tissue), 592 histidine
(identified in liver), 708 lysine (identified in the central
nervous system), 759 threonine (identified in central
nervous system), 780 valine (identified in central
nervous system), 795 isoleucine (identified in upper
aerodigestive tract). Mutations at aa 118 and 185 are in
the substrate domain, 407 and 430 are amino-terminal
to the 4 helical bundle, 583 and 592 are in the 4-helix
bundle, whereas 759, 780 and 795 localize to the Cterminal domain.
Homology
There is a family containing four proteins related to
BCAR1 (breast cancer resistance) that possess
names related to the prior nomenclature for BCAR1
homologs in the rat and mouse.
The non-human homologs of BCAR1 were named
CAS for Crk-associated substrate.
This family of proteins includes the protein EFS
(embryonal Fyn-associated substrate) (CAS3, CASS3,
EFS1, EFS2, HEFS, SIN) identified because of
interactions with the Src-family kinases Fyn and Yes
and maps to chromosome 14q11.2-q12.
A third family member is HEF1 (human enhancer of
filamentation 1 known as CASL, CAS-L, NEDD9,
CAS2 and CASS2) that maps to chromosome 6p25-p24
and was isolated as a human gene that promotes
filamentous growth in yeast. This screen was
performed to identify regulators of the cell cycle and
polarity.
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5)
Implicated in
Various cancers
Note
Overexpression of BCAR1 is linked to poor prognosis
and increased cancer metastasis in many cancers.
BCAR1 can be upregulated by gene amplification,
transcriptional upregulation and changes in protein
stability. Hyperphosphorylation of BCAR1 drives cell
migration, invasion, cell survival and drug resistance.
331
BCAR1 (breast cancer anti-estrogen resistance 1)
Berrier A
Figure 3. Extracellular cues that control CAR1 phosphorylation and cellular processes that are regulated by BCAR1.
poor prognosis correlate with overexpression of
BCAR1 and reductions in E-cadherin and β-catenin
levels (Guo et al., 2008).
Breast cancer
Prognosis
In breast cancers that express high levels of BCAR1,
the cancer is more likely to relapse and the tumors
frequently have an intrinsic reduced response to
tamoxifen (van der Flier et al., 2000; Dorssers et al.,
2004).
Oncogenesis
Elevated BCAR levels in breast cancers correlates with
increased expression of HER2/neu and enhanced cell
proliferation (Cabodi et al., 2006; Cabodi et al., 2010).
BCAR1 overexpression in breast cancer cells is linked
to resistance to the cytotoxic agent Adriamycin (Ta et
al., 2008). BCAR1 overexpression is sufficient to
induce hyperplasia in the mammary pad during
development and pregnancy.
Nasal polyps
Oncogenesis
Nasal polyps can express high levels of BCAR1 (Zhang
et al., 2003).
Colorectal cancer
Oncogenesis
Celecoxib cytotoxicity in colorectal cancer is linked to
cleavage of BCAR1 and apoptosis. Overexpression of
BCAR1 in colorectal cancer cell lines is linked to
resistance to celecoxib (Casanova et al., 2006; Weyant
et al., 2000).
Non-small-cell lung cancer (NSCLC)
Prostate cancer
Oncogenesis
BCAR1 is not detected in normal lung tissue, however
in non-small-cell lung cancer and tuberculosis and
other pulmonary disorders elevated levels of BCAR1
are observed in both the diseased tissue and elevated
levels are noted in serum (Deng et al., 2011). In
patients with NSCLC the serum levels of BCAR1
proportionally increase with the progression of tumor
stage. Interestingly, in patients with elevated serum
BCAR1 levels, the serum levels of BCAR1 diminish
after removal of the pulmonary lesion or tumor.
Oncogenesis
In prostate cancer, BCAR1 expression is higher
compared to control tissue and expression of BCAR1 in
prostate cancer correlates with elevated EGFR
expression levels (Fromont et al., 2007; Fromont et al.,
2011; Cabodi et al., 2010).
Hepatocellular carcinoma
Prognosis
In hepatocellular carcinoma, tumor invasion and
Atlas Genet Cytogenet Oncol Haematol. 2012; 16(5)
332
BCAR1 (breast cancer anti-estrogen resistance 1)
Berrier A
BCAR1 phosphorylation to promote the uptake of the
organism in non-phagocytic cells (Weidow et al.,
2000). S. typhimurium is an obligate intracellular
bacterial pathogen that requires eukaryotic cellular
uptake for infection. These bacteria utilize host
eukaryotic BCAR1 for efficient bacterial uptake and
their infectious cycle (Shi et al., 2006). In addition to
bacteria, many viruses also utilize the host protein
machinery and BCAR1 for their viral propagation. For
instance, internalization of adenovirus is initiated by
virus binding to host integrin receptors and virus
internalization requires BCAR1 phosphorylation (Li et
al., 1998; Li et al., 2000).
Ovarian cancer
Prognosis
In ovarian cancer, an increase in BCAR1 expression
correlates with poor 5 year survival rates and
reductions in BCAR1 expression result in reduced
tumor growth following docetaxel chemotherapy (Nick
et al., 2011).
Oral cancer
Oncogenesis
In oral cancers elevated levels of UPAR are indicative
of more invasive tumors and enhanced lymph node
metastasis. The levels of UPAR in oral cancer correlate
with the levels of BCAR1 (Shi et al., 2011).
References
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Oncogenesis
In anaplastic large-cell lymphomas, the anaplastic
lymphoma kinase (ALK) is frequently translocated and
a fusion protein with nucleophosmin (NPM)-ALK is
generated that contains kinase activity. NPM-ALK
transforms fibroblasts, however in BCAR1-/fibroblasts NPM-ALK fails to induce transformation.
Hence, BCAR1 is critical for ALK transformation
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Chemotherapeutic resistance
Note
Overexpression of BCAR1 is linked to drug resistance
in multiple tumor types such as breast cancer, lung
cancers, glioblastoma and melanoma (Ta et al., 2008).
BCAR1 and NEDD9 interact with BCAR3 to mediate
anti-estrogen resistance and to control Rap1 GTPase
activation (Cai et al., 2003). In a screen of an estrogen
dependent cell line, BCAR1 was identified as a gene
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Note
BCAR1 dysfunction is linked to inflammatory
disorders, ischemic stroke (Ziemka-Nalecz et al., 2007;
Zalewska et al., 2005) and developmental defects.
Knockout of BCAR1 is lethal at embryonic stages days
11,5 to 12,5 as a result of cardiovascular dysfunction
(Honda et al., 1998). BCAR1 is critical for the
pathology of many infectious diseases. The bacterial
species Yersinia encodes and secretes a phosphatase
YOP that inactivates/dephosphorylates BCAR1 and
YOP activity minimizes phagocytosis by macrophages
and neutrophils facilitating Yersinia evasion of
components of the cellular immune response which
disrupts clearance of the bacteria by the host (Deleuil et
al., 2003; Hamid et al., 1999). In contrast, in epithelial
cells,
Yersinia
uptake
is
associated
with
phosphorylation of BCAR1, thus the bacterium triggers
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