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IGF-IR cooperates with ER? to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules.


ABSTRACT: IGF-IR is highly associated with the behaviour of breast cancer cells. In ER?-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ER?-positive breast cancer cell aggressiveness and the regulation of expression levels of several extracellular matrix molecules. In particular, activation of IGF-IR, but not EGFR, in MCF-7 breast cancer cells results in the reduction of specific matrix metalloproteinases and their inhibitors. In contrast, IGF-IR inhibition leads to the depletion by endocytosis of syndecan-4. Global important changes in cell adhesion receptors, which include integrins and syndecan-4 triggered by IGF-IR inhibition, regulate adhesion and invasion. Cell function assays that were performed in MCF-7 cells as well as their ER?-suppressed counterparts indicate that ER status is a major determinant of IGF-IR regulatory role on cell adhesion and invasion. The strong inhibitory role of IGF-IR on breast cancer cells aggressiveness for which E2-ER? signaling pathway seems to be essential, highlights IGF-IR as a major molecular target for novel therapeutic strategies.

SUBMITTER: Afratis NA 

PROVIDER: S-EPMC5228153 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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IGF-IR cooperates with ERα to inhibit breast cancer cell aggressiveness by regulating the expression and localisation of ECM molecules.

Afratis Nikolaos A NA   Bouris Panagiotis P   Skandalis Spyros S SS   Multhaupt Hinke A HA   Couchman John R JR   Theocharis Achilleas D AD   Karamanos Nikos K NK  

Scientific reports 20170112


IGF-IR is highly associated with the behaviour of breast cancer cells. In ERα-positive breast cancer, IGF-IR is present at high levels. In clinical practice, prolonged treatment with anti-estrogen agents results in resistance to the therapy with activation of alternative signaling pathways. Receptor Tyrosine Kinases, and especially IGF-IR, have crucial roles in these processes. Here, we report a nodal role of IGF-IR in the regulation of ERα-positive breast cancer cell aggressiveness and the regu  ...[more]

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