The characterization of a mouse mutant that displays abnormal
mammary gland development
Beatrice A. Howard, Barry A. Gusterson
Institute of Cancer Research, The Breakthrough Toby Robins Breast Cancer Research Centre, Section of Cell Biology and Experimental Pathology,
237 Fulham Road, London SW3 6JB, UK
Received: 27 January 1999 / Accepted: 21 October 1999
Deficiencies and supernumerary mammary glands in inbred strains
of mice have been reported and were postulated to have a genetic
basis (Gardner and Strong 1935; Little and McDonald 1965). Here
we describe a naturally occurring mouse mutation named
scaramanga that displays abnormal embryonic and postnatal mam-
mary gland development found in the A/J strain of mice. We have
performed a genetic analysis of this mutation and have determined
that a single autosomal recessive locus appears to be responsible
for this trait.
The question of how body patterns are formed is a central
theme of developmental biology. Little is known about the mo-
lecular events that specify the site of organ development within a
larger, morphologically indistinguishable region. In mice, five
pairs of mammary glands are arranged in an ordered array along
the ventral surface between the forelimbs and hindlimbs. How this
order and spacing are achieved is unknown. Like many other or-
gans, the mammary gland develops as a result of reciprocal epi-
thelial-mesenchymal interactions (Cunha and Hom 1996); the cel-
lular and molecular mechanisms of these cell-cell interactions in
the mammary glands at the molecular level are poorly understood.
Epithelial-mesenchymal interactions also control postnatal growth
and ductal branching morphogenesis of the mammary gland
(Cunha and Hom 1996). It is thought that perturbations of epithe-
lial-mesenchymal interactions in adulthood may play a role in
carcinogenesis (Cunha 1994). Since breast cancer is a major cause
of mortality of women in developed countries, a better basic un-
derstanding of mammary gland development would be useful.
Abnormalities in human breast development exist that are
characterized by additional nipples (supernumerary), the presence
of additional breasts (polymastia), the absence of breasts (amastia),
the abnormal positioning of breasts, and the presence of more than
one nipple per breast (polythelia; Klinkerfuss 1924; Gates 1946;
Fraser 1956; Goldenring and Crelin 1961). Supernumerary nipples
and polymastia have been reported in many mammals, including
mice, sheep, guinea pigs, as well as humans (Bell 1898; Goertzen
and Ibsen 1951). Polymastia and supernumerary nipples can be
sporadic, but when occurring as an hereditary trait, behave in an
autosomal dominant fashion in humans and in guinea pigs
(Klinkerfuss 1924; Gates 1946; Goertzen and Ibsen 1951). Mouse
mutants and human syndromes have been described that display
multiple developmental defects that include abnormal mammary
gland development. Ulnar-mammary syndrome and scalp-ear-
nipple syndromes affect a variety of other organs as well as the
mammary gland (Finlay and Marks 1978; Edwards et al. 1994;
Bamshad et al. 1995). There are reports of an increased incidence
of renal and urological abnormalities and renal carcinomas with
the presence of supernumerary nipples in humans (Meggyessy and
Mehes 1987; Urbani and Betti 1995).
A few mouse mutants display aberrant mammary gland devel-
opment during the early stages of mammary gland formation.
Mammary gland development is incomplete or abrogated before
morphogenesis in both Lef1- and p63-deficient mice (van Gen-
deren et al. 1994; Mills et al. 1999; Yang et al. 1999). Both para-
thyroid hormone-related protein (PTHrP) knockout mice and para-
thyroid hormone (PTH)/PTHrP receptor knockout mice fail to un-
dergo the initial round of branching growth that is responsible for
transforming the mammary bud into the rudimentary duct system,
and no mammary epithelial ducts or nipple structures form
(Wysolmerski et al. 1998). Studies of other mouse mutants that
display abnormal mammary gland formation in early patterning
should lead to further insights into how pattern is initially gener-
ated in these specialized structures.
Most wild and inbred strains of mice, including the C57BL/6J
(or B6) strain, have 10 nipples (Fig. 1A). Three pairs of thoracic
(#1, #2, and #3) and two pairs of inguinal mammary glands (#4
and #5) are present in a linear order on the ventral surface of the
female mouse. However, we have observed that the A/J inbred
strain of mice displays abnormal mammary development. A/J mice
display supernumerary mammary glands and nipples, misplaced
nipples, and mammary gland deficiencies (Fig. 1B, Table 1).
Ninety-five percent of A/J mice display a mammary gland pattern
phenotype. We have not observed any other developmental defects
in these mice, and it is possible that a novel gene is involved. We
have used classical genetic analysis to study this gene, which we
have named ska (for scaramanga).
Correspondence to: B.A. Howard, e-mail: email@example.com
Fig. 1. Mammary gland development in the B6 and A/J strains of mice.
Mammary glands are numbered from 1 to 5. (A) In adult female B6 mice,
five pairs of mammary glands are evenly spaced along the ventral surface.
(B) In adult female A/J mice, abnormal mammary development occurs; in
this case, an absent left #3 mammary gland is displayed, which is indicated
by an arrow.
Mammalian Genome 11, 234–237 (2000).
© Springer-Verlag New York Inc. 2000