Cs. Atwood et al., Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice, J ENDOCR, 167(1), 2000, pp. 39-52
Development of the functional secretory epithelium in the mammary gland of
the female mouse requires the elongation of the anlage through the mammary
fat pad to form the primary/secondary ductal network from which tertiary du
ctal side-branches and lobuloalveoli develop. In this study we examined the
hormonal requirements for the spatial development of the primary/secondary
epithelial network and tertiary side-branches by quantifying ductal growth
and epithelial cell proliferation in normal and hormone-treated BALB/c mic
e between 21 and 39 days of age. In normal mice, an allometric increase in
ductal length commenced at 31 days of age and resulted in completion of the
primary/secondary ductal network by 39 days of age. Concurrent with this a
llometric growth was a significant increase in cellular proliferation in th
e terminal end-buds (TEBs) of the ductal epithelium from 29 days of age, as
determined by 5-bromo-2'-deoxyuridine (BrdU) incorporation. A level of cel
lular proliferation similar to that in the TEBs of 33-day-old control mice
could be induced in the TEBs of 25-day-old mice following treatment for 1 d
ay with estrogen (E), or progesterone (P) or both (E/P), indicating that bo
th E and P were mitogenic for epithelial cells of the peripubertal TEBs. Ho
wever, die period of allometric ductal growth in untreated mice did not cor
respond to an increase in serum E or P (which might have been expected duri
ng the estrous cycle). In addition, epithelial growth was not observed in m
ammary glands from 24-day-old mice that were cultured in vitro with E, P or
E/P. In contrast to treatment with E, treatment with P promoted a dramatic
increase, relative to control mice, in the number of tertiary branch point
s upon the primary/secondary ductal network. BrdU labeling of mammary gland
s from 24-33-day-old mice pelleted with cholesterol (C), E, P or E/P confir
med the greater mitogenicity of P on the epithelial cells of the secondary/
tertiary ducts as compared with C or E. Concurrent with these changes, loca
lized progesterone receptor (PR) expression in clusters of cells in the duc
tal epithelium was associated with structures that histologically resembled
early branch points from ductules. In conclusion, our results suggest that
additional endocrine growth factor(s) other than E and P contribute to the
development of the primary/secondary ductal network, and that P is respons
ible for the formation of tertiary side-branches in the mammary glands of m
ice during puberty.