The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas

Mai Tran; Shoshana A Leflein; Maria E Gonzalez; Celina G Kleer

doi:10.1007/s12079-021-00657-9

The matricellular protein CCN6 differentially regulates mitochondrial metabolism in normal epithelium and in metaplastic breast carcinomas

J Cell Commun Signal. 2022 Sep;16(3):433-445. doi: 10.1007/s12079-021-00657-9. Epub 2021 Nov 22.

Authors

Mai Tran^{1

2}, Shoshana A Leflein^{1

2}, Maria E Gonzalez^{1

2}, Celina G Kleer^{3

4}

Affiliations

¹ Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA.
² Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.
³ Department of Pathology, 4217 Rogel Cancer Center, University of Michigan Medical School, 1500 E. Medical Center Dr., Ann Arbor, MI, 48109, USA. kleer@umich.edu.
⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA. kleer@umich.edu.

Abstract

Metaplastic breast carcinoma (MBC) is an aggressive subtype of triple negative breast cancer with undefined precursors, limited response to chemotherapy, and frequent distant metastasis. Our laboratory has reported that CCN6/WISP3, a secreted protein that regulates growth factor signaling, is downregulated in over 85% of MBCs. Through generation of a mammary epithelial cell-specific Ccn6 knockout mouse model (MMTV-cre;Ccn6^fl/fl) we have demonstrated that CCN6 is a tumor suppressor for MBC; MMTV-cre;Ccn6^fl/fl mice develop tumors recapitulating the histopathology and proteogenomic landscape of human MBC, but the mechanisms need further investigation. In this study, we report that preneoplastic mammary glands of 8-week-old MMTV-Cre;Ccn6^fl/fl female mice show significant downregulation of mitochondrial respiratory chain genes compared to controls, which are further downregulated in MBCs of MMTV-Cre;Ccn6^fl/fl mice and humans. We found that CCN6 downregulation in non-tumorigenic breast cells reduces mitochondrial respiration and increases resistance to stress-induced apoptosis compared to controls. Intracellular ectopic CCN6 protein localizes to the mitochondria in MDA-MB-231 mesenchymal-like breast cancer cells, increases mitochondrial respiration and generation of reactive oxygen species, and reverses doxorubicin resistance of MBC cells. Our data highlight a novel function of CCN6 in the regulation of redox states in preneoplastic progression and suggest potential preventative and treatment strategies against MBC based on CCN6 upregulation.

Keywords: CCN6; Initiation; Metaplastic carcinoma; Mitochondrial metabolism; Prevention; TNBC; Triple negative; WISP3.

Abstract

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