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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.

Show MeSH
Model for different phases of mammary gland branching morphogenesis. Before puberty, the mammary epithelial is small and simply branched. In response to the release of estrogen (E) and growth hormone (GH), at ∼3 wk old TEBs form. MMP-2 is then involved in inducing TEBs to invade and the ducts begin to fill the fat pad by branching dichotomously through bifurcation. At ∼6–8 wk old, the mammary ducts branch laterally. This process is suppressed by MMP-2 and induced by MMP-3 and may be related to changes in the response of the gland to progesterone (P) and prolactin (PRL). The fat pad is filled with ducts at ∼10 wk old and is relatively quiescent until pregnancy, when there is another wave of lateral branching that is regulated by MMP-3, P, and PRL before the formation of lobular alveoli.
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fig6: Model for different phases of mammary gland branching morphogenesis. Before puberty, the mammary epithelial is small and simply branched. In response to the release of estrogen (E) and growth hormone (GH), at ∼3 wk old TEBs form. MMP-2 is then involved in inducing TEBs to invade and the ducts begin to fill the fat pad by branching dichotomously through bifurcation. At ∼6–8 wk old, the mammary ducts branch laterally. This process is suppressed by MMP-2 and induced by MMP-3 and may be related to changes in the response of the gland to progesterone (P) and prolactin (PRL). The fat pad is filled with ducts at ∼10 wk old and is relatively quiescent until pregnancy, when there is another wave of lateral branching that is regulated by MMP-3, P, and PRL before the formation of lobular alveoli.

Mentions: MMP-2 regulates the initial invasion of TEBs into the fat pad. MMP-2 has been implicated in the induction of apoptosis through destruction of ECM, leading to altered adhesion (anoikis; Lund et al., 1996; Roberts et al., 2002) or by allowing infiltration of toxic immune cells (Wielockx et al., 2001). In contrast, MMP-2 promotes cell survival in the TEB, which is a site of both proliferation and cell death. Thus, MMP-2 may release survival factors sequestered by binding proteins or the ECM. However, TEBs are multilayered and the apoptotic cells are found close to the lumen (Fig. 6; Humphreys et al., 1996), which suggests that these cells are not dying by anoikis. Thus, other potential substrates, such as insulin-like growth factor binding proteins, which are MMP-2 substrates (Fowlkes et al., 1999) that can be inhibited from signaling in vivo by MMP inhibitors (Martin et al., 1999), may be responsible for the survival-promoting effects of MMP-2. The enlarged TEBs of the TIMP-1–deficient mammary glands may also be related to a reduction in apoptosis due to increased MMP-2 activity, leading to an overabundance of cells. MMP-2 presumably allows sufficient cells to accumulate for ductal extension to ensue. Although it is likely that cell migration is important for branching and the invasion of the epithelial cell layer into the fat pad, our results suggest that branches may be pushed outwards by cell division. This does not preclude the possibility that they are also pulled out by migratory cells.


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)

Model for different phases of mammary gland branching morphogenesis. Before puberty, the mammary epithelial is small and simply branched. In response to the release of estrogen (E) and growth hormone (GH), at ∼3 wk old TEBs form. MMP-2 is then involved in inducing TEBs to invade and the ducts begin to fill the fat pad by branching dichotomously through bifurcation. At ∼6–8 wk old, the mammary ducts branch laterally. This process is suppressed by MMP-2 and induced by MMP-3 and may be related to changes in the response of the gland to progesterone (P) and prolactin (PRL). The fat pad is filled with ducts at ∼10 wk old and is relatively quiescent until pregnancy, when there is another wave of lateral branching that is regulated by MMP-3, P, and PRL before the formation of lobular alveoli.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Model for different phases of mammary gland branching morphogenesis. Before puberty, the mammary epithelial is small and simply branched. In response to the release of estrogen (E) and growth hormone (GH), at ∼3 wk old TEBs form. MMP-2 is then involved in inducing TEBs to invade and the ducts begin to fill the fat pad by branching dichotomously through bifurcation. At ∼6–8 wk old, the mammary ducts branch laterally. This process is suppressed by MMP-2 and induced by MMP-3 and may be related to changes in the response of the gland to progesterone (P) and prolactin (PRL). The fat pad is filled with ducts at ∼10 wk old and is relatively quiescent until pregnancy, when there is another wave of lateral branching that is regulated by MMP-3, P, and PRL before the formation of lobular alveoli.
Mentions: MMP-2 regulates the initial invasion of TEBs into the fat pad. MMP-2 has been implicated in the induction of apoptosis through destruction of ECM, leading to altered adhesion (anoikis; Lund et al., 1996; Roberts et al., 2002) or by allowing infiltration of toxic immune cells (Wielockx et al., 2001). In contrast, MMP-2 promotes cell survival in the TEB, which is a site of both proliferation and cell death. Thus, MMP-2 may release survival factors sequestered by binding proteins or the ECM. However, TEBs are multilayered and the apoptotic cells are found close to the lumen (Fig. 6; Humphreys et al., 1996), which suggests that these cells are not dying by anoikis. Thus, other potential substrates, such as insulin-like growth factor binding proteins, which are MMP-2 substrates (Fowlkes et al., 1999) that can be inhibited from signaling in vivo by MMP inhibitors (Martin et al., 1999), may be responsible for the survival-promoting effects of MMP-2. The enlarged TEBs of the TIMP-1–deficient mammary glands may also be related to a reduction in apoptosis due to increased MMP-2 activity, leading to an overabundance of cells. MMP-2 presumably allows sufficient cells to accumulate for ductal extension to ensue. Although it is likely that cell migration is important for branching and the invasion of the epithelial cell layer into the fat pad, our results suggest that branches may be pushed outwards by cell division. This does not preclude the possibility that they are also pulled out by migratory cells.

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