Type I collagen and DDR1 axis has been described to decrease cell proliferation and to initiate apoptosis in non-invasive breast carcinoma in three-dimensional cell culture matrices. Moreover, MT1-MMP down-regulates these effects. Here, we address the effect of type I collagen aging and MT1-MMP expression on cell proliferation suppression and induced-apoptosis in non-invasive MCF-7 and ZR-75-1 breast carcinoma. We provide evidence for a decrease in cell growth and an increase in apoptosis in the presence of adult collagen when compared to old collagen. This effect involves a differential activation of DDR1, as evidenced by a higher DDR1 phosphorylation level in adult collagen. In adult collagen, inhibition of DDR1 expression and kinase function induced an increase in cell growth to a level similar to that observed in old collagen. The impact of aging on the sensitivity of collagen to MT1-MMP has been reported recently. We used the MT1-MMP expression strategy to verify whether, by degrading adult type I collagen, it could lead to the same phenotype observed in old collagen 3D matrix. MT1-MMP overexpression abrogated the proliferation suppression and induced-apoptosis effects only in the presence of adult collagen. This suggests that differential collagen degradation by MT1-MMP induced a structural disorganization of adult collagen and inhibits DDR1 activation. This could in turn impair DDR1-induced cell growth suppression and apoptosis. Taken together, our data suggest that modifications of collagen structural organization, due to aging, contribute to the loss of the growth suppression and induced apoptosis effect of collagen in luminal breast carcinoma. MT1-MMP-dependent degradation and aging of collagen have no additive effects on these processes.

中文翻译：

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I型胶原蛋白的年龄相关修饰会损害DDR1诱导的非侵入性乳腺癌细胞凋亡。

I型胶原蛋白和DDR1轴已被描述为减少三维细胞培养基质中非浸润性乳腺癌的细胞增殖并引发细胞凋亡。而且，MT1-MMP下调了这些作用。在这里，我们解决了非侵入性MCF-7和ZR-75-1乳腺癌中I型胶原蛋白老化和MT1-MMP表达对细胞增殖抑制和诱导凋亡的影响。我们提供证据，与旧胶原蛋白相比，在成人胶原蛋白存在下细胞生长减少和凋亡增加。这种作用涉及DDR1的差异激活，成人胶原蛋白中较高的DDR1磷酸化水平证明了这一点。在成人胶原蛋白中，DDR1表达和激酶功能的抑制导致细胞生长增加，达到与旧胶原蛋白相似的水平。最近已经报道了老化对胶原蛋白对MT1-MMP敏感性的影响。我们使用MT1-MMP表达策略来验证是否可以通过降解成人I型胶原蛋白来导致在旧的3D胶原蛋白基质中观察到相同的表型。MT1-MMP过表达仅在存在成人胶原蛋白的情况下才消除了增殖抑制和诱导的细胞凋亡作用。这表明MT1-MMP对胶原蛋白的不同降解会诱导成人胶原蛋白的结构紊乱，并抑制DDR1活化。这反过来可能会损害DDR1诱导的细胞生长抑制和凋亡。两者合计，我们的数据表明，胶原蛋白结构组织的修饰，由于衰老，导致腔内乳腺癌中胶原蛋白的生长抑制作用丧失和诱导的凋亡作用。