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Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis.

Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ, Soloway P, Itohara S, Werb Z - J. Cell Biol. (2003)

Bottom Line: Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty.In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy.Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

ABSTRACT
During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

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TIMP-1 is not necessary for ductal invasion or branching in the mammary gland. (A and B) Whole mounts of mammary glands of 42-d-old TIMP-1 +/+ (A) and TIMP-1 −/− mice (B). Note the enlarged TEBs of TIMP-1 −/− mice (inset). Bars, 1 mm. (C and D) Penetration of mammary ducts into fat pad (C) and number of branch points beyond the lymph node at 42 d old (D) of TIMP-1 +/+ and TIMP-1 −/− mice. Data are mean (C) ± SEM or (D) ± SD using four to eight mammary glands per data point.
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fig3: TIMP-1 is not necessary for ductal invasion or branching in the mammary gland. (A and B) Whole mounts of mammary glands of 42-d-old TIMP-1 +/+ (A) and TIMP-1 −/− mice (B). Note the enlarged TEBs of TIMP-1 −/− mice (inset). Bars, 1 mm. (C and D) Penetration of mammary ducts into fat pad (C) and number of branch points beyond the lymph node at 42 d old (D) of TIMP-1 +/+ and TIMP-1 −/− mice. Data are mean (C) ± SEM or (D) ± SD using four to eight mammary glands per data point.

Mentions: If inhibition of MMP activity attenuates mammary ductal invasion, then the absence of TIMP-1 could reduce MMP action and change mammary morphogenesis. TIMP-1 mRNA is up-regulated during mouse mammary gland pubertal development (Fata et al., 1999), but we found no change in primary duct elongation in TIMP-1 −/− mice compared with controls, and only small increases in the number of branch points (Fig. 3 D). This is not surprising because at least three TIMP family members are expressed in the mammary gland. However, TEBs were much larger in TIMP-1 −/− mice than their wild-type littermates (Fig. 3 B), indicating that TIMP-1 contributes to maintenance of TEB morphology.


Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis.

Wiseman BS, Sternlicht MD, Lund LR, Alexander CM, Mott J, Bissell MJ, Soloway P, Itohara S, Werb Z - J. Cell Biol. (2003)

TIMP-1 is not necessary for ductal invasion or branching in the mammary gland. (A and B) Whole mounts of mammary glands of 42-d-old TIMP-1 +/+ (A) and TIMP-1 −/− mice (B). Note the enlarged TEBs of TIMP-1 −/− mice (inset). Bars, 1 mm. (C and D) Penetration of mammary ducts into fat pad (C) and number of branch points beyond the lymph node at 42 d old (D) of TIMP-1 +/+ and TIMP-1 −/− mice. Data are mean (C) ± SEM or (D) ± SD using four to eight mammary glands per data point.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172848&req=5

fig3: TIMP-1 is not necessary for ductal invasion or branching in the mammary gland. (A and B) Whole mounts of mammary glands of 42-d-old TIMP-1 +/+ (A) and TIMP-1 −/− mice (B). Note the enlarged TEBs of TIMP-1 −/− mice (inset). Bars, 1 mm. (C and D) Penetration of mammary ducts into fat pad (C) and number of branch points beyond the lymph node at 42 d old (D) of TIMP-1 +/+ and TIMP-1 −/− mice. Data are mean (C) ± SEM or (D) ± SD using four to eight mammary glands per data point.
Mentions: If inhibition of MMP activity attenuates mammary ductal invasion, then the absence of TIMP-1 could reduce MMP action and change mammary morphogenesis. TIMP-1 mRNA is up-regulated during mouse mammary gland pubertal development (Fata et al., 1999), but we found no change in primary duct elongation in TIMP-1 −/− mice compared with controls, and only small increases in the number of branch points (Fig. 3 D). This is not surprising because at least three TIMP family members are expressed in the mammary gland. However, TEBs were much larger in TIMP-1 −/− mice than their wild-type littermates (Fig. 3 B), indicating that TIMP-1 contributes to maintenance of TEB morphology.

Bottom Line: Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty.In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy.Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.

ABSTRACT
During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

Show MeSH
Related in: MedlinePlus