Tumorigenesis is a complex and poorly understood process in which oncogenes can activate competing proapoptotic and proneoplastic programs. A recent paper in Cancer Cell demonstrates a dual role of the MTDH-SND1 complex in suppressing the apoptotic response and promoting breast cancer development, suggesting a new therapeutic avenue

Eaves, Connie J.

Kannan, Nagarajan

Elsevier - Publisher Connector 

Cell Stem Cell
PreviewsVerma, 2014). Somatic cells likely mount
barriers to reprogramming to avoid
cellular transformation. Hence, it will be
interesting to see whether newly iden-
tified roadblocks are also implicated in
cancer development. At the moment it
is unclear whether the small overlap of
hits between the two studies is due
to the species difference, the different
markers used to isolate cell populations,
or the studies not being comprehensive.
In support of the latter explanation, it
should be noted that several known re-
programming factors were not identified
in the screens. For instance, in a similar
approach Rais et al. found that Mbd3
RNAi together with OSKM transduction
results in deterministic and synchronized
iPSC reprogramming (Rais et al., 2013).
However, Mbd3 was identified in neither
the Qin et al. nor the Yang et al. studies.
Therefore, extended RNAi screens will
likely uncover even more genes that influ-
ence the efficiency and kinetics of iPSC
generation. In any event, the presented
data should broaden our understanding
of the underlying mechanisms of reprog-
raming. The challenging part will now
be to combine reprogramming barriers
whose combinatorial inhibition will have118 Cell Stem Cell 15, August 7, 2014 ª2014the largest impact on enhancing reprog-
ramming efficacy and kinetics. In addi-
tion, it will be important to see whether
the identified factors are fibroblast spe-
cific or if they are also roadblocks for
reprogramming in other somatic cells.
Recent studies have revealed contradict-
ing results for factors implicated in
reprogramming, where one group has
found that Mbd3 depletion promotes re-
programming (Rais et al., 2013), whereas
another group described that Mbd3
is required for efficient reprogramming
(Dos Santos et al., 2014). There were a
number of differences between the two
experimental approaches that might ac-
count for this discrepancy. Nevertheless,
this example illustrates the necessity
to conduct detailed experiments under
varying conditions to investigate the
molecular mechanisms that operate
during reprogramming. Therefore, the
development of an optimized protocol
demands a careful downstream anal-
ysis and a thorough investigation of
the reprogrammed iPSCs, including the
evaluation of their functionality as well
as the verification of their genomic and
epigenomic integrity (Liang and Zhang,
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Cell Reports, in press. Published online July 17,
2014.Tipping the Balance: MTDH-SND1
Curbs Oncogene-Induced Apoptosis
and Promotes TumorigenesisNagarajan Kannan1 and Connie J. Eaves1,*
1Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
*Correspondence: ceaves@bccrc.ca
http://dx.doi.org/10.1016/j.stem.2014.07.010
Tumorigenesis is a complex and poorly understood process in which oncogenes can activate competing
proapoptotic and proneoplastic programs. A recent paper in Cancer Cell demonstrates a dual role of the
MTDH-SND1 complex in suppressing the apoptotic response and promoting breast cancer development,
suggesting a new therapeutic avenue.Tumorigenesis is a complex process in
which cells typically acquire mutations
that do not initially alter their biology, but
ultimately lead to their transition into a
state characterized by the possession ofself-perpetuating, malignant properties.
Several distinct molecular programs may
contribute to this transition, but our
knowledge of this aspect of oncogenesis
is poor, particularly in epithelial carci-nomas that are frequently not detected
until after they are well established and
often disseminated. Elucidating the rele-
vant events that influence the speed and
ability of individual cells to achieve this
Figure 1. The MTDH-SND1 Prosurvival Complex Influences the Likelihood of the Creation of
Tumorigenic Cells and the Maintenance of the Viability of Their Progeny
Oncogenic mutations in normal cells activate molecular programs involved in oncogenesis and the
regulation of cell survival. The oncogenic stress response that activates the cell death machinery can
be mitigated if the prosurvival MTDH-SND1 complex is intact (left cartoon). Disruption or blockade of
the formation of this complex reduces the frequency of cells that acquire andmaintain tumorigenic activity
(right panel).
Cell Stem Cell
Previewsstate is of major interest, because the
knowledge gainedmay provide new clues
for developing improved cancer therapies
or even strategies for cancer prevention.
In the normal adult female mammary
gland, two types of epithelial cells, an
outer basal layer and an inner luminal
layer of epithelial cells, must execute
a combination of survival, proliferation,
self-renewal, and differentiation programs
to meet changing physiological demands.
In humans (Kannan et al., 2013, 2014) and
likely in mice (Artandi et al., 2000; Diehn
et al., 2009), this results in the creation
in situ of cells that are highly prone
to mutagenesis, potentially increasing
their probability of subsequent malignant
transformation. Recently in Cancer Cell,
Kang and colleagues describe a new
mechanism that antagonizes both the
oncogene-activated and DNA-damage-
enhanced sensitivities to apoptosis that
are already apparent in the preneoplas-
tic cells generated in multiple models
of breast cancer induction. Interestingly,
disrupting this mechanismwas also found
to determine the probability and pace of
subsequent tumor formation (Wan et al.,
2014).Metadherin (MTDH; also known as
Astrocyte elevated gene 1 (AEG1)) is a lit-
tle-studied gene located on human chro-
mosome 8q22, a region that is frequently
amplified in many cancers including those
arising in the breast. Kang and colleagues
now demonstrate that loss of MTDH
delays the appearance of tumors in four
different mouse models of breast can-
cer (three different oncogene- and one
carcinogen-induced model) consistent
with a documented reduction in the fre-
quency of cells with operationally defined,
transplantable ‘‘tumor-initiating cell’’ (TIC)
activity. More detailed analyses showed
that loss of MTDH also increased the
frequency of apoptotic cells selectively
among either basal or luminal mammary
cells, depending on which subset was
undergoing oncogene-activated hyper-
plastic transformation. Because the au-
thors had previously shown that MTDH
forms a stable intracellular complex with
Staphylococcal nuclease domain-con-
taining 1 (SND1), itself a known prosur-
vival factor (Blanco et al., 2011), their
next step was to use a vector-mediated
shRNA knockdown approach to examine
the potential role of SND1 in mediatingCell Stem Cell 1the same effects caused by loss of
MTDH. What they found was that, in the
same breast cancer induction models,
loss of either component of the complex
phenocopies loss of the other (Figure 1).
Through additional experiments that iden-
tified a specific SND1-binding motif in
MTDH, Wan et al. (2014) were also able
to show that disruption of the interaction
between these two proteins was sufficient
to erode the prosurvival roles of either one
in oncogene-stressed mammary epithe-
lial cells.
The authors also created an Mtdh-
knockout-LacZ-knockin mouse. Exami-
nation of the females revealed MTDH to
be a ubiquitously expressed protein but
one, nevertheless, that is not required for
normal mouse development or fertility,
nor for the formationof a normalmammary
gland. Using an assay in which the mam-
mary stem cells are enumerated based
on their ability to regenerate a complete
new gland when transplanted at limiting
dilutions into the mammary fat pad of
new female host mice, Wan et al. (2014)
further showed that neither the production
nor the regenerative activity of this primi-
tive subset of normal mammary cells is
dependent on the MTDH-SND1 complex.
Together these findings suggest that
MTDH is not essential for the homeostatic
control or functionality of any normal
mammary epithelial cell type, either basal
or luminal. On the other hand, in both of
these cell types, the MTDH-SND1 com-
plex plays an important role in reducing
the proapoptotic effect of oncogene
activation, even before the cells begin
to display fully malignant properties.
Importantly, Wan et al. (2014) also pro-
vide persuasive evidence that these find-
ings are relevant to human breast cancer.
They first demonstrate that reducing
MTDH or SND1 activity in either trans-
formed human breast cancer cell lines
or patient-derived xenografts decreases
the frequency of cells that initiate tumor
formation in vivo (in xenografted, immu-
nodeficient mice). In addition, analysis of
human breast cancer microarray data
sets revealed strongly correlated expres-
sion of these two proteins in individual
patients’ tumors and an inverse correla-
tion between their expression and the
response of the tumor to standard ther-
apy. These findings suggest that expres-
sion of these markers is indicative of a
bad prognosis in human breast cancer.5, August 7, 2014 ª2014 Elsevier Inc. 119
Cell Stem Cell
PreviewsThe molecular mechanisms through
which the MTDH-SND1 complex protects
cells against oncogenic stress will be very
interesting to investigate in the future.
Amplified MTDH has also been reported
to enhance breast cancer tumor cell
metastasis, raising the question of how
this is achieved. Since SND1 has been
shown to be a component of the multi-
protein RNA-induced silencing complex
(RISC), where it has a stabilizing function
(Tsuchiya et al., 2007), it may be inter-
esting to explore the possibility that
the MTDH-SND1 complex could influ-
ence microRNA expression.
An important aspect of the study by
Wan et al. (2014) is their finding that
MTDH is expressed in many tissues.
This suggests that the role of the MTDH-
SND1 complex in breast cancer formation
may be shared by tumors in other tissues,
such as the liver and colon (Huang et al.,
2014; Yoo et al., 2009). In addition, the
results of Wan et al. (2014) illustrate
how important, and potentially clinically
exploitable, insights can be gained from
analyzing early events in tumorigenesis,
here exemplified by the identification
of a cell-intrinsic mechanism that ap-
pears to promote oncogene/carcinogen-120 Cell Stem Cell 15, August 7, 2014 ª2014induced tumorigenesis by reducing a
coinduced proapoptotic response. Antia-
poptotic mechanisms are well-known to
play a key role in the creation of a malig-
nant state; for example, via mutations
in BCL2, TP53, and MYC (Cotter, 2009).
However, these latter examples have usu-
ally been associated with the blockade
of an apoptotic mechanism that normally
serves to control mature cell numbers in
the tissue. In contrast, the antiapoptotic
mechanism of interest here appears to
act indirectly by enhancing the probability
that a cell will survive deleterious effects
of genomic perturbation. The evidence
suggesting that increased expression
of the MTDH-SND1 complex in human
breast cancer is an indicator of poor
prognosis suggests the possibility of
targeting this complex for therapeutic
intervention, and the identified interac-
tion site between MTDH and SND1 pro-
vides a potential starting point for such
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Tipping the Balance: MTDH-SND1 Curbs Oncogene-Induced Apoptosis and Promotes Tumorigenesis 

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Tipping the Balance: MTDH-SND1 Curbs Oncogene-Induced Apoptosis and Promotes Tumorigenesis

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