Let-7 microRNA controls invasion-promoting lysosomal changes via the oncogenic transcription factor myeloid zinc finger-1

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Siri Amanda Tvingsholm, Malene Bredahl Hansen, Knut Kristoffer Bundgaard Clemmensen, Ditte Marie Brix, Bo Rafn, Lisa B. Frankel, Riku Louhimo, José Moreira, Sampsa Hautaniemi, Irina Gromova, Marja Jäättelä, Tuula Kallunki

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.

Original languageEnglish
Article number14
JournalOncogene
Volume7
Issue number2
Pages (from-to)1-15
Number of pages15
ISSN0950-9232
DOIs
Publication statusPublished - 2018

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