Cellular senescence of human mammary epithelial cells (HMEC) is associated with an altered MMP-7/HB-EGF signaling and increased formation of elastin-like structures |
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Authors: | Catharina Bertram Ralf Hass |
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Affiliation: | aClinic of Obstetrics and Gynecology, Biochemistry and Tumor Biology Lab (OE6411), Medical School, Carl-Neuberg-Street 1, D – 30625 Hannover, Germany |
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Abstract: | The extracellular matrix (ECM) and a complex interplay of cell-to-cell and cell-to-matrix (ECM) interactions provide important platforms to determine cellular senescence and a potentially tumorigenic transformation of normal human mammary epithelial cells (HMEC). An enhanced formation of extracellular filaments, consisting of elastin-like structures, in senescent post-selection HMEC populations was paralleled by a significantly increased expression of its precursor protein tropoelastin and matched with a markedly elevated activity of the cross-linking enzyme family of lysyl oxidases (LOX). RNAi experiments revealed both the ECM metalloproteinase MMP-7 and the growth factor HB-EGF as potential effectors of an increased tropoelastin expression. Moreover, co-localization of MMP-7 and HB-EGF as well as a concomittant downstream signaling via Fra-1 indicated a possible association between the reduced MMP-7 enzyme activity and an impaired HB-EGF processing, resulting in an enhanced tropoelastin synthesis during senescence of HMEC. In agreement with previous work, these findings suggested an important influence of the extracellular proteinase MMP-7 on the aging process of HMEC, affecting both extracellular remodeling as well as intracellular signaling pathways. |
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Keywords: | Aging Breast cancer Cellular senescence Extracellular matrix Matrix metalloproteinases |
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