Mammary Gland 'Remembers' Prior Pregnancy, Spurring Milk Production

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Mammary gland 'remembers' priorpregnancy, spurring milk production

May 7, 2015

Cold Spring Harbor Laboratory

Anecdotal reports of nursing mothers have long suggestedthat giving milk is a lot easier in second and subsequentpregnancies, compared with a first pregnancy. Now,researchers can explain why. Their work shows themammary gland forms a long-term memory of pregnancy thatprimes it to respond to the hormonal changes that announcesucceeding pregnancies.

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mammary gland in previously pregnant mice responds earlier andproduces more branching ductal structures, used in lactation. Newresearch shows breast tissue retains a cellular memory of priorpregnancy that makes response more rapid and vigorous in subsequentpregnancies.

Credit: Image courtesy of Cold Spring Harbor Laboratory

Anecdotal reports of nursing mothers have longsuggested that giving milk is a lot easier in secondand subsequent pregnancies, compared with a firstpregnancy. Now, researchers at Cold SpringHarbor Laboratory (CSHL) are able to explain why.

Their work shows the mammary gland forms a long-term memory ofpregnancy that primes it to respond to the hormonal changes thatannounce succeeding pregnancies. The memory lasts throughout anindividual's reproductive years. The results appear online in Cell Reports.

Secretion of the hormones estrogen and progesterone set the stage fordramatic changes that take place in the breast during pregnancy: amassive proliferation of mammary epithelial cells, and the formation ofthousands of ductal structures, which support milk production and transportduring lactation.

A team led by HHMI Investigator Greg Hannon, a CSHL Professor and alsoa Professor and Senior Group Leader at the CRUK Cambridge Institute atthe University of Cambridge, hypothesized that pregnancy might alter the

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gland's receptiveness to pregnancy-related hormones. Specifically, theysought to determine if this might occur via changes in a set of chemicalmarks that attach to DNA, the genetic material. Such marks -- molecules ofmethyl (CH3), for instance -- are called epigenetic marks, and theirpresence or absence in particular locations in the genome can eitherprevent genes from being expressed, or promote their expression.

Camila dos Santos, now a CSHL Assistant Professor, developed atechnique critical to the newly reported experiments when she was apostdoctoral investigator in the Hannon lab. Dos Santos found a marker ofmammary stem cells that enabled her to isolate highly purified stem cells inaddition to a number of other cell types specific to the mouse mammarygland -- six in all. From these, she generated genome-wide profiles ofwhere methyl groups attach to the DNA. Of all the epigenetic marks, methylmarks tend to be the longest lasting, and are often permanent.

Working with Andrew Smith, a computational biologist from the University ofSouthern California, they found that cells sampled from young mice thathad been through a single pregnancy cycle had methylation marks thatwere "substantially different" from marks in cells sampled from mice of thesame age that had never been pregnant. "Of those changes," saysHannon, "we were able to trace a majority to places in the genome where asingle transcription factor, called Stat5a, binds. This is really remarkable --so many changes in methylation, and you can track them down to a singlefactor." Like all transcription factors, Stat5a binds to DNA and in so doingchanges the way a specific gene or genes are expressed.

The team shows that a first pregnancy erases many methyl marks that arepresent throughout life leading up to pregnancy. During a first pregnancy,the team suggests, Stat5a binds DNA in certain types of mammaryepithelial cells, at places near genes that need to be activated during

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pregnancy -- specifically, genes involved in proliferation and lactation. Asthe team showed in mice, when a once-pregnant female receiveshormones whose action simulates a real pregnancy, the mice respondmore rapidly than other, never-pregnant mice given the same hormones. Inthe previously pregnant mice, "the mammary glands start expanding fasterand also sooner than for those experiencing pregnancy hormones for thefirst time," says dos Santos. "It's as if the gland already knows thosehormones."

"This is an example of epigenetic memory: it is the loss of DNA methylationthat is now marking sites in the genome that were active in a previouspregnancy," dos Santos says. When the same sites were examined a yearafter pregnancy (or exposure to pregnancy hormones), they remainedunoccupied by methyl marks. "The cell is not replenishing DNA methylationat these sites, even after several cell divisions, which means the memory ofprevious pregnancy is long-term."

These findings have led to another important line of research. It is wellknown that women who become pregnant by age 25 have substantiallylower rates of breast cancer than women who bear children later in life ornot at all. It is possible that the implied protective factor is in some wayrelated to the epigenetic memory of mammary cells just discovered,Hannon says.

Dos Santos says her lab is now "trying to understand which of themodifications we found in this study might prevent development of breastcancer in a pregnancy-related manner."

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Cite This Page :

Cold Spring Harbor Laboratory. "Mammary gland 'remembers' priorpregnancy, spurring milk production." ScienceDaily. ScienceDaily, 7 May2015. .

The above story is based on materials provided by Cold Spring HarborLaboratory. The original article was written by Peter Tarr. Note: Materialsmay be edited for content and length.

Journal Reference :

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

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Mammary Gland 'Remembers' Prior Pregnancy, Spurring Milk Production