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Brain Cancer Worries?

Mammary gland 'remembers' prior

pregnancy, spurring milk production
Date:
Source:
Summary:

May 7, 2015

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Cold Spring Harbor Laboratory

Anecdotal reports of nursing mothers have long suggested
that giving milk is a lot easier in second and subsequent
pregnancies, compared with a first pregnancy. Now,
researchers can explain why. Their work shows the
mammary gland forms a long-term memory of pregnancy that
primes it to respond to the hormonal changes that announce
succeeding pregnancies.

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Usurps Powers of
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These images show the effect of pregnancy hormones after 6 and 12

days on breast tissue in mice that have never been pregnant (top row)
and mice that have been pregnant once before (bottom row). The
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mammary gland in previously pregnant mice responds earlier and

produces more branching ductal structures, used in lactation. New
research shows breast tissue retains a cellular memory of prior
pregnancy that makes response more rapid and vigorous in subsequent
pregnancies.
Credit: Image courtesy of Cold Spring Harbor Laboratory

Anecdotal reports of nursing mothers have long

suggested that giving milk is a lot easier in second
and subsequent pregnancies, compared with a first
pregnancy. Now, researchers at Cold Spring
Harbor Laboratory (CSHL) are able to explain why.
Their work shows the mammary gland forms a long-term memory of
pregnancy that primes it to respond to the hormonal changes that
announce succeeding pregnancies. The memory lasts throughout an
individual's reproductive years. The results appear online in Cell Reports.
Secretion of the hormones estrogen and progesterone set the stage for
dramatic changes that take place in the breast during pregnancy: a
massive proliferation of mammary epithelial cells, and the formation of
thousands of ductal structures, which support milk production and transport
during lactation.
A team led by HHMI Investigator Greg Hannon, a CSHL Professor and also
a Professor and Senior Group Leader at the CRUK Cambridge Institute at
the University of Cambridge, hypothesized that pregnancy might alter the
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prolactin is also produced by some

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gland's receptiveness to pregnancy-related hormones. Specifically, they

sought to determine if this might occur via changes in a set of chemical
marks that attach to DNA, the genetic material. Such marks -- molecules of
methyl (CH3), for instance -- are called epigenetic marks, and their
presence or absence in particular locations in the genome can either
prevent genes from being expressed, or promote their expression.
Camila dos Santos, now a CSHL Assistant Professor, developed a
technique critical to the newly reported experiments when she was a
postdoctoral investigator in the Hannon lab. Dos Santos found a marker of
mammary stem cells that enabled her to isolate highly purified stem cells in
addition to a number of other cell types specific to the mouse mammary
gland -- six in all. From these, she generated genome-wide profiles of
where methyl groups attach to the DNA. Of all the epigenetic marks, methyl
marks tend to be the longest lasting, and are often permanent.
Working with Andrew Smith, a computational biologist from the University of
Southern California, they found that cells sampled from young mice that
had been through a single pregnancy cycle had methylation marks that
were "substantially different" from marks in cells sampled from mice of the
same age that had never been pregnant. "Of those changes," says
Hannon, "we were able to trace a majority to places in the genome where a
single transcription factor, called Stat5a, binds. This is really remarkable -so many changes in methylation, and you can track them down to a single
factor." Like all transcription factors, Stat5a binds to DNA and in so doing
changes the way a specific gene or genes are expressed.
The team shows that a first pregnancy erases many methyl marks that are
present throughout life leading up to pregnancy. During a first pregnancy,
the team suggests, Stat5a binds DNA in certain types of mammary
epithelial cells, at places near genes that need to be activated during
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pregnancy -- specifically, genes involved in proliferation and lactation. As

the team showed in mice, when a once-pregnant female receives
hormones whose action simulates a real pregnancy, the mice respond
more rapidly than other, never-pregnant mice given the same hormones. In
the previously pregnant mice, "the mammary glands start expanding faster
and also sooner than for those experiencing pregnancy hormones for the
first time," says dos Santos. "It's as if the gland already knows those
hormones."
"This is an example of epigenetic memory: it is the loss of DNA methylation
that is now marking sites in the genome that were active in a previous
pregnancy," dos Santos says. When the same sites were examined a year
after pregnancy (or exposure to pregnancy hormones), they remained
unoccupied by methyl marks. "The cell is not replenishing DNA methylation
at these sites, even after several cell divisions, which means the memory of
previous pregnancy is long-term."
These findings have led to another important line of research. It is well
known that women who become pregnant by age 25 have substantially
lower rates of breast cancer than women who bear children later in life or
not at all. It is possible that the implied protective factor is in some way
related to the epigenetic memory of mammary cells just discovered,
Hannon says.
Dos Santos says her lab is now "trying to understand which of the
modifications we found in this study might prevent development of breast
cancer in a pregnancy-related manner."

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The above story is based on materials provided by Cold Spring Harbor

Laboratory. The original article was written by Peter Tarr. Note: Materials
may be edited for content and length.

Journal Reference:
1. Gregory J. Hannon et al. An Epigenetic Memory of Pregnancy in
the Mouse Mammary Gland. Cell Reports, May 2015 DOI:
10.1016/j.celrep.2015.04.015

Cite This Page:

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Cold Spring Harbor Laboratory. "Mammary gland 'remembers' prior

pregnancy, spurring milk production." ScienceDaily. ScienceDaily, 7 May
2015. <www.sciencedaily.com/releases/2015/05/150507122850.htm>.

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