Gary M.K. Tse

Julia Y.S. Tsang

EBioMedicine

PubMed

Tsang, Julia Y.S.

Tse, Gary M.K.

Elsevier - Publisher Connector 

Is BECN1 a Target Gene of Chromosome 17q21 Alteration in Breast Cancer? 

Directory of Open Access Journals

Is BECN1 a Target Gene of Chromosome 17q21 Alteration in Breast Cancer?

EBioMedicine 2 (2015) 190–191
Contents lists available at ScienceDirect
EBioMedicine
j ourna l homepage: www.eb iomed ic ine.comCommentaryIs BECN1 a Target Gene of Chromosome 17q21 Alteration in Breast Cancer?Julia Y.S. Tsang, Gary M.K. Tse⁎
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative RegionIn this issue of EBioMedicine, Tang et al. describes their results ob- tumour formation due to mammary gland-speciﬁc biallelic Palb2 dele-
tained from analysing the expression of BRCA1 and BECN1 in breast can-
cer patients from two large datasets (TCGA and METABRIC datasets)
(Tang et al., 2015). They found reproducible associations in both
datasets of BECN1 expression with oestrogen receptor negative cancers
(HER2-OE and basal like breast cancers) as well as molecular features
related to the subtypes. Intriguingly, no such correlations were found
with BRCA1 expression. A similar relationship was also observed in the
analysis of BRCA1 deletion cases. In addition, BECN1, but not BRCA1,
was shown to be an independent prognostic factor in multivariate
analysis.
Both BECN1 and BRCA1 are closely located on 17q21, a region fre-
quently deleted in sporadic breast cancers. For many years, BRCA1 has
attracted much more attention in breast cancer than BECN1. BRCA1 en-
codes a multifunctional protein that plays key roles in DNA repair, cell
cycle control and transcriptional regulation (Turner et al., 2007). Muta-
tions in BRCA1 are well known to be responsible for the development of
familial breast cancer. Although BRCA1 dysfunction has been linked also
to basal-like breast cancer, it is important to note that it is mainly based
on studies from familial cases with BRCA1 mutation. These cancers
shared many phenotypes and gene expression signature associated
with basal like breast cancers, suggesting similarities in pathogenic
mechanisms (Turner et al., 2007). Although these have been corrobo-
rated by some studies in sporadic cancers, controversy still exists
among different studies (Rakha et al., 2008).
BECN1 is an essential regulator of autophagy. BECN1, with its close
proximity with BRCA1, is frequently co-deleted with BRCA1 (Turner
et al., 2004). Given that it is a haplo-insufﬁcient tumour-suppressor,
its co-deletion with BRCA1 may also contribute to mammary tumori-
genesis and cancer characteristics attributable to BRCA1 dysfunction.
However, its role in breast cancer remains debatable and may depend
on cellular context. Mono-allelic deletion of BECN1 in C67/B6 mice has
led to the formation of spontaneous lung and liver cancers as well as
lymphoma but only mammary hyperplasia (Qu et al., 2003). However,
different results were obtained from other breast cancer models. In
ERBB2- or PyMT-driven mammary tumorigenesis, there are no effects
of monoallelic deletion of BECN1 (Lozy et al., 2014); whereas it delaysDOI of original article: http://dx.doi.org/10.1016/j.ebiom.2015.01.008.
⁎ Corresponding author at: Department of Anatomical and Cellular Pathology, Prince of
Wales Hospital, NganShing Street, Shatin, Hong Kong Special Administrative Region.
E-mail address: garytse@cuhk.edu.hk (G.M.K. Tse).
http://dx.doi.org/10.1016/j.ebiom.2015.02.012
2352-3964/© 2015 The Authors. Published by Elsevier B.V. This is an open access article undertion in a wild-type Tp53 background (Huo et al., 2013). In contrast,
monoallelic BECN1 loss can promote mammary tumour formation fol-
lowing parity and in Wnt1-driven oncogenesis (Cicchini et al., 2014).
The ﬁndings may indicate that the interactions of BECN1 with various
cellular pathways can result in different consequences. Regarding the
relationship of BECN1 with speciﬁc breast cancer subtypes, so far,
there is very limited information available. Of note, in Wnt1 mouse
model, the tumour developed has been shown to exhibit basal
cytokeratin upregulation aswell as augmentation of mammary progen-
itor cell activities, i.e. characteristic of basal-like breast cancer (Cicchini
et al., 2014). It is also interesting to note that there could be some syn-
ergies in functional roles of BECN1 and BRCA1. As for BRCA1, recent
ﬁndings have suggested the involvement BECN1 in the maintenance
of genomic integrity (Mathew et al., 2007) and regulation of oestrogen
receptor signalling (John et al., 2008).
In all, BECN1 could have potential signiﬁcance in breast cancers that
have not been fully appreciated previously. However, its precise roles in
breast cancer biology remain elusive. Breast cancer is a heterogeneous
disease comprised of different subtypes with different underlying biol-
ogy. As shown by the different ﬁndings from various model systems,
functional impacts of BECN1 alteration could be context dependent. Ex-
amination and evaluation of large datasets in light with signalling path-
way alterationswithin different breast cancerswill be necessary to have
a clear understanding of clinical impacts as well as biology of BECN1 al-
terations. In fact, when Tang et al. stratiﬁed BECN1 expression into three
expression levels, the intermediate groups did not show a consistent
outcome in different subgroups of breast cancers, possibly reﬂecting
the different biology underlying this group in contrast to the low and
high BECN1 expressing cases. The clinico-pathological characteristic
and nature of this group in comparison with the others remains to be
explored, in particular in different subgroups of breast cancers. Findings
from Tang et al. suggested the prognostic implication of BECN1mRNA
contributed to the pathogenesis of breast cancer. However, the applica-
tion of mRNA prognostic marker in routine clinical practice still has
some limitations. It would be interesting to explore whether similar
ﬁndings could be also observed with BECN1 protein expression. While
transcriptional deregulation of BECN1 appears to play a signiﬁcant role
in breast cancer pathogenesis, other post-transcriptional regulatory
mechanisms could be involved in BRCA1 deregulation, for example, ab-
errant subcellular localisation and deregulation in protein expression of
BRCA1 (Rakha et al., 2008). The contribution of BRCA1 deregulation in
the pathogenesis of breast cancer cannot be ruled out. Evaluation onthe CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
191J.Y.S. Tsang, G.M.K. Tse / EBioMedicine 2 (2015) 190–191their protein expressions and other regulatory mechanisms will be es-
sential to draw a more deﬁnitive conclusion on their respective signiﬁ-
cance in breast cancer.
Disclosure
The authors disclosed no conﬂicts of interest.
References
Cicchini, M., Chakrabarti, R., Kongara, S., Price, S., Nahar, R., Lozy, F., et al., 2014. Autophagy
regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation
and following parity. Autophagy 10 (11), 2036–2052.
Huo, Y., Cai, H., Teplova, I., Bowman-Colin, C., Chen, G., Price, S., et al., 2013. Autophagy op-
poses p53-mediated tumor barrier to facilitate tumorigenesis in a model of PALB2-
associated hereditary breast cancer. Cancer Discov. 3 (8), 894–907.
John, S., Nayvelt, I., Hsu, H.C., Yang, P., Liu, W., Das, G.M., et al., 2008. Regulation of estro-
genic effects by beclin 1 in breast cancer cells. Cancer Res. 68 (19), 7855–7863.Lozy, F., Cai-McRae, X., Teplova, I., Price, S., Reddy, A., Bhanot, G., et al., 2014. ERBB2 over-
expression suppresses stress-induced autophagy and renders ERBB2-induced mam-
mary tumorigenesis independent of monoallelic Becn1 loss. Autophagy 10 (4),
662–676.
Mathew, R., Kongara, S., Beaudoin, B., Karp, C.M., Bray, K., Degenhardt, K., et al., 2007. Au-
tophagy suppresses tumor progression by limiting chromosomal instability. Genes
Dev. 21 (11), 1367–1381.
Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., et al., 2003. Promotion of
tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin.
Invest. 112 (12), 1809–1820.
Rakha, E.A., El-Sheikh, S.E., Kandil, M.A., El-Sayed,M.E., Green, A.R., Ellis, I.O., 2008. Expres-
sion of BRCA1 protein in breast cancer and its prognostic signiﬁcance. Hum. Pathol.
39 (6), 857–865.
Tang, H., Sebti, S., Titone, R., Zhou, Y., Isidoro, C., Ross, T., et al., 2015. Decreased expression
fo BECN1 in breast cancer is associated with ER-negative subtypes and poor progno-
sis. EBioMedicine http://dx.doi.org/10.1016/j.ebiom.2015.01.008.
Turner, N., Tutt, A., Ashworth, A., 2004. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat.
Rev. Cancer 4 (10), 814–819.
Turner, N.C., Reis-Filho, J.S., Russell, A.M., Springall, R.J., Ryder, K., Steele, D., et al., 2007.
BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26 (14),
2126–2132.


http://dx.doi.org/10.1016/j.ebiom.2015.02.012

Is BECN1 a Target Gene of Chromosome 17q21 Alteration in Breast Cancer?

Abstract

Similar works

Full text

Available Versions

Elsevier - Publisher Connector

Directory of Open Access Journals

Elsevier - Publisher Connector