Mammary Gland Cells Formed During Maternity Have Stem Cell Properties
A class of cells that arises in mammary glands during maternity
has stem cell-like properties, according to findings by researchers
at the National Cancer Institute (NCI), part of the National Institutes
of Health. These parity-induced mammary epithelial cells (PI-MEC)
have the ability to self-renew over many generations and to differentiate
into numerous cellular subtypes. These results, appearing in Oncogene*
online on December 6, 2004, also demonstrate that PI-MEC growth
can be curtailed by expression of the growth factor TGF-beta1, potentially
providing a mechanism for prevention of some types of breast cancer.
In mice, rats, and humans, pregnancy has a dual effect on the risk
of breast cancer. It is known that a full-term pregnancy early in
adulthood reduces the long-term risk of breast cancer; however,
during each pregnancy there is a transient, short-term increase
in breast cancer risk. The alteration of the mammary tissue during
pregnancy likely provides the basis for these risk effects, although
the exact mechanisms remain unclear.
Gilbert H. Smith, Ph.D., in NCI's Mammary Biology and Tumorigenesis
Laboratory, and Kay-Uwe Wagner, Ph.D., at the University of Nebraska
Medical School, had previously co-discovered a new subtype of mammary
epithelial cells present only in mice that had given birth. Starting
around the third trimester of pregnancy, these cells expanded and
contributed to the formation of mammary ducts and lobules. "After
lactation, a vast majority of these cells die," said Smith,
"but we saw remnants hanging along the ends of the ducts. During
subsequent pregnancies, these ancestors get reactivated and form
new milk-secreting lobules." Smith and Wagner also observed
that these PI-MEC were targets for transformation into cancer cells
when mice were exposed to mouse mammary tumor virus during multiple
pregnancies.
Smith's new findings help explain why these cells might facilitate
tumor formation. Since PI-MEC act as ancestors for mammary growth,
Smith and his lab examined how much growth and differentiation potential
these cells had. They performed serial transplantations of bits
of mammary tissue and observed that PI-MEC (specially marked so
they can stain blue) were able to stay in the tissue over a length
of four transplants, which corresponds to about 40 doublings. The
researchers also transplanted PI-MEC into mice and then initiated
pregnancy to examine mammary outgrowth. They discovered that the
marked PI-MEC could differentiate into all the epithelial subtypes
present in mammary tissue.
"PI-MEC have two critical features of stem cells," said
Smith, "self-renewal of their population, and the ability to
produce progeny of multiple cellular subtypes." Smith, however,
did point out that PI-MEC did not exhibit the full developmental
capacity of true stem cells, as additional experiments showed that
PI-MEC only expanded and differentiated when they were in contact
with other epithelial cell types. "Still, these cells are more
likely to expand than other cells during pregnancy, and that increased
expansion increases the risk of cancer development," said Smith.
However, when Smith and his lab targeted the expression of TGF-beta1
to PI-MEC, they observed that these cells could no longer rapidly
proliferate and maintain themselves in serial transplants of mammary
tissue. In pregnant females, TGF-beta1 expression slowed down PI-MEC
differentiation and increased the rate of cell death, leading to
incomplete development of the secretory lobules. These mice could
not lactate, but they were also protected from breast cancer development
when infected by mouse mammary tumor virus.
"Importantly, though," said Smith, "we only observed
this effect when we induced TGF-beta1 expression within the cells.
Adding external growth factor did not produce the same result. This
is an important point to consider for any treatment or prevention
measures."
For more information about cancer, visit the NCI Web site at
http://www.cancer.gov
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* Boulanger CA, Wagner K, Smith GH. Parity-induced
mojse mammary epithelial cells are pluripotent, self-renewing and
sensitive to TGF-beta 1 expression. Oncogene. Published online December
6, 2004. |