INSIGHTS | PERSPECTIVES
By Claire Robertson
The ability of certain adult stem cell types to differentiate into other cell types, expand massively, or quiesce until needed underlies the study of development and of how cells grow uncontrollably in cancer. Adult stem
cell behavior in many organs depends on
unique, protected microenvironments harboring specialized extracellular matrix proteins, support
cells, hormones, or other factors
collectively called stem cell niches
(1, 2). But what, exactly, constitutes
a stem cell niche? On page 284 of
this issue, Zhao et al. (3) report an
element of the mammary gland stem
cell niche that drives local expansion
and growth of the epithelial compartment in response to global hormones. Select fibroblast cells that are
peripheral to the stem cells “
translate” hormones into signals that stem
The adult mammary gland is
composed of a network of epithelial
ducts and lobules that synthesize
and transport milk and is embedded
in the stroma of the mammary fat
pad. The epithelial portion expands
in response to hormones during
puberty or lactation, an ability conferred by abundant adult stem cells.
These stem cells can differentiate
into the two cell types that consti-
tute the duct system—luminal epi-
thelial and myoepithelial cells (1). Although
mammotropic hormones, such as proges-
terone and estrogen, stimulate mammary
epithelial growth and expansion, mammary
stem cells appear to be insensitive to them
(4, 5). Thus, growth of mammary stem cells
poses a conundrum. Mature epithelial cells
can sense these hormones and secrete fac-
tors that stimulate mammary stem cell
expansion (4, 5). However, control of epithe-
lial growth does not depend on the epithelia
alone; nonepithelial supportive tissue of the
mammary gland (stroma) also controls the
extent of epithelial expansion and branch-
ing (6). But how could stroma control mam-
mary stem cells in response to hormones?
Glioma-associated oncogene family zinc
finger 2 (GLI2), a hedgehog pathway transcription factor, appears to link abnormal
breast development and tumorigenesis (7) to
the stroma of the mammary gland. Zhao et al.
report that loss of GLI2 in a mouse model resulted in abnormal, hypoplastic development
of epithelial tissue and the loss of epithelial
regenerative capability, indicators of aberrant
mammary stem cell function.
Surprisingly, Zhao et al. discovered that
mouse mammary epithelial cells do not ex-
press this transcription factor. Instead, GLI2
was expressed in a subpopulation of stromal
fibroblasts that are closely associated with
the outside of epithelial ducts, but do not di-
rectly contact epithelia. This fibroblast popu-
lation in vivo responded to growth hormone
or estrogen stimulation by secreting multiple
growth factors, including insulin-like growth
factor 1 (IGF1), hepatocyte growth factor
(HGF), and several wingless-related integra-
tion site proteins (WNTs), along with extra-
cellular matrix proteins. Among these many
factors, IGF1 and WNT2B that were released
from a polymer implanted in the mammary
gland rescued mammary development in
mice lacking GLI2. Collectively, the results
suggest that hormone-driven provision of
growth factors by stromal fibroblasts is es-
sential to mammary stem cell niche function.
Communication between stroma and epi-
thelia, and the question of how stem cell pop-
ulations are maintained in adult organs, take
on a new urgency when considering cancer
development. A common hypothesis holds
that cancers arise from relatively
immature cell types (8); thus, the
number and potency of stem cells in
an organ may be linked to the prob-
ability of developing cancer in that
organ (9). Patients with congenital
growth hormone receptor mutations
(Laron syndrome) do not develop
cancers (10), whereas overabun-
dance of IGF1 or growth hormones is
linked to cancer aggressiveness (11),
suggesting that stroma–mammary
stem cell communication through
this mechanism may also occur in
humans. Indeed, genetic background
of the stroma can alter breast tumor
susceptibility independently of the
genetic background of the epithelia
even though the tumor arises from
epithelial cells (6).
That a specific subpopulation of
fibroblasts mediates hormone sensing in the breast is thus an exciting
mechanism that links stroma to epithelial growth (see the figure). Altering the number of mammary stem
cells or their growth and differentiation potential through stroma–stem
cell communication may afford a mechanism
for chemoprevention in addition to explaining mammary underdevelopment observed
in growth hormone deficiencies. j
REFERENCES AND NOTES
1. J. L. Inman et al ., Development 142, 1028 (2015).
2. A. D. Lander et al ., BMC Biol. 10, 19 (2012).
3. C. Zhao et al., Science 356, eaal3485 (2017).
4. M.-L. Asselin-Labat et al., Nature 465, 798 (2010).
5. P.A.Joshi et al., Nature 465,803(2010).
6. P. Zhang et al ., Sci. Rep.5, 8919 (2015).
7. M. T. Lewis et al., J. Mammary Gland Biol. Neoplasia 9, 165
8. J. E. Visvader,Nature 469, 314 (2011).
9. C. Tomasetti,B.Vogelstein, Science 347,78(2015).
10. O. Shevah, Z. Laron, Growth Horm.IGFRes. 17, 54 (2007).
11. Z. Laron, Mech.Ageing Dev. 126, 305 (2005).
C.R. is funded by the U.S. Department of Defense Congressionally
Directed Medical Research Program (BC133875).
Biological Systems and Engineering, Lawrence
Berkeley National Lab, Berkeley, CA 94720, USA.
A network of epithelial ducts
expands in response to puberty
In response to hormones,
luminal epithelial cells
and stromal fbroblasts that
express GLI2 release factors
that stimulate stem cells
to expand and diferentiate.
activator of nuclear
factor kappa-B ligand.
Luminal epithelial cell
Decoding hormones for a stem cell niche
Stromal cells in the mammary gland enable stem cells to respond to hormones
250 21 APRIL 2017 • VOL 356 ISSUE 6335
Decoding hormone signals
Epithelial and stromal cells secrete factors in response to global
hormones such as estrogen and progesterone. Mammary stem cells
then respond to these secreted factors.