Limits...
Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β.

Parvani JG, Galliher-Beckley AJ, Schiemann BJ, Schiemann WP - Mol. Biol. Cell (2013)

Bottom Line: We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts.Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β.Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin-deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106.

ABSTRACT
Mammary tumorigenesis and epithelial-mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin-deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin-specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.

Show MeSH

Related in: MedlinePlus

Model of the dichotomous roles of β1 and β3 integrins in mediating breast cancer metastasis. Integrin switching between β1 and β3 integrins in metastatic 4T1 cells uncouples TGF-β from down-regulating E-cadherin expression, thereby attenuating the acquisition of EMT and migratory phenotypes. Elevated expression of MMP-9 and VEGF is associated with this integrin switching event and contributes to autocrine TGF-β signaling and activation of compensatory EMT programs. The physiological distribution of vitronectin expression may selectively mediate the pulmonary outgrowth of cells that underwent β1 → β3 integrin switching.
© Copyright Policy - creative-commons
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3814150&req=5

Figure 8: Model of the dichotomous roles of β1 and β3 integrins in mediating breast cancer metastasis. Integrin switching between β1 and β3 integrins in metastatic 4T1 cells uncouples TGF-β from down-regulating E-cadherin expression, thereby attenuating the acquisition of EMT and migratory phenotypes. Elevated expression of MMP-9 and VEGF is associated with this integrin switching event and contributes to autocrine TGF-β signaling and activation of compensatory EMT programs. The physiological distribution of vitronectin expression may selectively mediate the pulmonary outgrowth of cells that underwent β1 → β3 integrin switching.

Mentions: The acquisition of metastatic phenotypes in breast cancers correlates with elevated levels of TGF-β signaling and include essential inputs derived from β1 and β3 integrins (Taylor et al., 2010; Parvani et al., 2011). The objective of this study was to determine whether inhibiting the oncogenic functions of TGF-β by targeted inactivation of β1 integrin could be circumvented by compensatory expression of β3 integrin. In addressing this question, we were surprised to observe minimal interplay between β1 and β3 integrins in normal, nontransformed MECs. In stark contrast, we identified an inherent β1 → β3 integrin switching mechanism that enabled metastatic breast cancer cells to bypass diminished β1 integrin signaling inputs via their ability to up-regulate β3 integrin expression, which maintains oncogenic TGF-β signaling (Figure 8). The up-regulation of β3 integrin expression by β1 integrin–deficient breast cancer cells depended on the activity of p38 MAPK (Figure 2), which presumably couples to HoxA10, CBP, or FoxC2 to elicit the synthesis of β3 integrin transcripts (Bei et al., 2007; Hayashi et al., 2008). Collectively these events culminate in the continued development and metastatic progression of aggressive triple-negative breast cancers (Figure 7). In addition to p38 MAPK activity, we also observed that elevated MMP-9 expression was associated with β1 → β3 integrin switching (Figure 3), which may account for the increased activation of Smads 2 and 3 (Figure 4) via the release of latent TGF-β and other growth factors from inactive extracellular matrix depots (Figure 8; Egeblad and Werb, 2002; Taylor et al., 2010). Although the mechanisms responsible for mediating these events remain to be fully elucidated, we suspect that either 1) inactivation of β1 integrin, which elevates the expression of Dab2 (J.G.P. and W.P.S., unpublished data), enhances TGF-β receptor recycling and Smad2/3 phosphorylation and activation (Penheiter et al., 2010); or 2) β1 integrin deficiency elevates TGF-β signaling by alleviating steric hindrance within β1 integrin:TβR-IIβ3 integrin complexes (Galliher and Schiemann, 2006), thereby enabling TβR-I to more efficiently access and activate Smad2/3. Of interest, we previously demonstrated that maximal coupling of TβR-II to β3 integrin required the latter to be activated by its preferred substrate, vitronectin (Galliher and Schiemann, 2006). Thus it is tempting to speculate that compensatory β3 integrin expression synergizes with vitronectin to enhance oncogenic TGF-β signaling during multiple stages of metastatic progression, including 1) intravasation, 2) survival during dissemination in the circulatory system, and 3) reinitiation of proliferation programs during metastatic outgrowth (Figure 8; Preissner, 1991).


Targeted inactivation of β1 integrin induces β3 integrin switching, which drives breast cancer metastasis by TGF-β.

Parvani JG, Galliher-Beckley AJ, Schiemann BJ, Schiemann WP - Mol. Biol. Cell (2013)

Model of the dichotomous roles of β1 and β3 integrins in mediating breast cancer metastasis. Integrin switching between β1 and β3 integrins in metastatic 4T1 cells uncouples TGF-β from down-regulating E-cadherin expression, thereby attenuating the acquisition of EMT and migratory phenotypes. Elevated expression of MMP-9 and VEGF is associated with this integrin switching event and contributes to autocrine TGF-β signaling and activation of compensatory EMT programs. The physiological distribution of vitronectin expression may selectively mediate the pulmonary outgrowth of cells that underwent β1 → β3 integrin switching.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3814150&req=5

Figure 8: Model of the dichotomous roles of β1 and β3 integrins in mediating breast cancer metastasis. Integrin switching between β1 and β3 integrins in metastatic 4T1 cells uncouples TGF-β from down-regulating E-cadherin expression, thereby attenuating the acquisition of EMT and migratory phenotypes. Elevated expression of MMP-9 and VEGF is associated with this integrin switching event and contributes to autocrine TGF-β signaling and activation of compensatory EMT programs. The physiological distribution of vitronectin expression may selectively mediate the pulmonary outgrowth of cells that underwent β1 → β3 integrin switching.
Mentions: The acquisition of metastatic phenotypes in breast cancers correlates with elevated levels of TGF-β signaling and include essential inputs derived from β1 and β3 integrins (Taylor et al., 2010; Parvani et al., 2011). The objective of this study was to determine whether inhibiting the oncogenic functions of TGF-β by targeted inactivation of β1 integrin could be circumvented by compensatory expression of β3 integrin. In addressing this question, we were surprised to observe minimal interplay between β1 and β3 integrins in normal, nontransformed MECs. In stark contrast, we identified an inherent β1 → β3 integrin switching mechanism that enabled metastatic breast cancer cells to bypass diminished β1 integrin signaling inputs via their ability to up-regulate β3 integrin expression, which maintains oncogenic TGF-β signaling (Figure 8). The up-regulation of β3 integrin expression by β1 integrin–deficient breast cancer cells depended on the activity of p38 MAPK (Figure 2), which presumably couples to HoxA10, CBP, or FoxC2 to elicit the synthesis of β3 integrin transcripts (Bei et al., 2007; Hayashi et al., 2008). Collectively these events culminate in the continued development and metastatic progression of aggressive triple-negative breast cancers (Figure 7). In addition to p38 MAPK activity, we also observed that elevated MMP-9 expression was associated with β1 → β3 integrin switching (Figure 3), which may account for the increased activation of Smads 2 and 3 (Figure 4) via the release of latent TGF-β and other growth factors from inactive extracellular matrix depots (Figure 8; Egeblad and Werb, 2002; Taylor et al., 2010). Although the mechanisms responsible for mediating these events remain to be fully elucidated, we suspect that either 1) inactivation of β1 integrin, which elevates the expression of Dab2 (J.G.P. and W.P.S., unpublished data), enhances TGF-β receptor recycling and Smad2/3 phosphorylation and activation (Penheiter et al., 2010); or 2) β1 integrin deficiency elevates TGF-β signaling by alleviating steric hindrance within β1 integrin:TβR-IIβ3 integrin complexes (Galliher and Schiemann, 2006), thereby enabling TβR-I to more efficiently access and activate Smad2/3. Of interest, we previously demonstrated that maximal coupling of TβR-II to β3 integrin required the latter to be activated by its preferred substrate, vitronectin (Galliher and Schiemann, 2006). Thus it is tempting to speculate that compensatory β3 integrin expression synergizes with vitronectin to enhance oncogenic TGF-β signaling during multiple stages of metastatic progression, including 1) intravasation, 2) survival during dissemination in the circulatory system, and 3) reinitiation of proliferation programs during metastatic outgrowth (Figure 8; Preissner, 1991).

Bottom Line: We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts.Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β.Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin-deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106.

ABSTRACT
Mammary tumorigenesis and epithelial-mesenchymal transition (EMT) programs cooperate in converting transforming growth factor-β (TGF-β) from a suppressor to a promoter of breast cancer metastasis. Although previous reports associated β1 and β3 integrins with TGF-β stimulation of EMT and metastasis, the functional interplay and plasticity exhibited by these adhesion molecules in shaping the oncogenic activities of TGF-β remain unknown. We demonstrate that inactivation of β1 integrin impairs TGF-β from stimulating the motility of normal and malignant mammary epithelial cells (MECs) and elicits robust compensatory expression of β3 integrin solely in malignant MECs, but not in their normal counterparts. Compensatory β3 integrin expression also 1) enhances the growth of malignant MECs in rigid and compliant three-dimensional organotypic cultures and 2) restores the induction of the EMT phenotypes by TGF-β. Of importance, compensatory expression of β3 integrin rescues the growth and pulmonary metastasis of β1 integrin-deficient 4T1 tumors in mice, a process that is prevented by genetic depletion or functional inactivation of β3 integrin. Collectively our findings demonstrate that inactivation of β1 integrin elicits metastatic progression via a β3 integrin-specific mechanism, indicating that dual β1 and β3 integrin targeting is necessary to alleviate metastatic disease in breast cancer patients.

Show MeSH
Related in: MedlinePlus