Abstract
Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger1 (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. Here we identify let-7 microRNA, a well-known tumor suppressor in breast cancer, as a direct negative regulator of MZF1. Analysis of primary breast cancer tissues reveals a gradual upregulation of MZF1 from normal breast epithelium to invasive ductal carcinoma and a negative correlation between several let-7 family members and MZF1 mRNA, suggesting that the inverse regulatory relationship between let-7 and MZF1 may play a role in the development of invasive breast cancer. Furthermore, we show that MZF1 regulates lysosome trafficking in ErbB2-positive breast cancer cells. In line with this, MZF1 depletion or let-7 expression inhibits invasion-promoting anterograde trafficking of lysosomes and invasion of ErbB2-expressing MCF7 spheres. The results presented here link MZF1 and let-7 to lysosomal processes in ErbB2-positive breast cancer cells that in non-cancerous cells have primarily been connected to the transcription factor EB. Identifying MZF1 and let-7 as regulators of lysosome distribution in invasive breast cancer cells, uncouples cancer-associated, invasion-promoting lysosomal alterations from normal lysosomal functions and thus opens up new possibilities for the therapeutic targeting of cancer lysosomes.
Highlights
Cancer cells utilize lysosomes for invasion and metastasis
Myeloid Zinc Finger1 (MZF1) expression is upregulated in human breast cancer We compared MZF1 protein expression in tissue microarrays (TMAs) containing 321 samples of normal breast tissue and different grades of primary breast cancer by quantitative immunohistochemistry (IHC)
In samples of more advanced invasive ductal carcinoma (IDC), the mean MZF1 expression remained increased when compared with normal breast epithelium samples (Fig. 1c)
Summary
Cancer cells utilize lysosomes for invasion and metastasis. Myeloid Zinc Finger[1] (MZF1) is an ErbB2-responsive transcription factor that promotes invasion of breast cancer cells via upregulation of lysosomal cathepsins B and L. In addition to the increased lysosomal cathepsin activity, ErbB2-induced invasion of breast and ovarian cancer cells involves anterograde trafficking of lysosomes: in response to ErbB2 activation the lysosome distribution changes from a normal perinuclear or scattered distribution to the cell periphery[13,14]. They can secrete their contents, including cathepsin B, by lysosomal exocytosis and induce invasion-promoting intracellular and extracellular degradation[13,15,16]. TFEB is, not involved in the CTSB upregulation induced by ErbB2 in breast cancer cells[13], suggesting that other transcription factors may regulate the anterograde trafficking of lysosomes in cancer cells
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