Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity

Cicchini, M., Chakrabarti, R., Kongara, S., Price, S., Nahar, R., Lozy, F., Zhong, H., Vazquez, A. , Kang, Y. and Karantza, V. (2014) Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy, 10(11), pp. 2036-2052. (doi: 10.4161/auto.34398) (PMID:25483966) (PMCID:PMC4502817)

Abstract

Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1+/−;MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

• Item Type: Articles
• Additional Information: We are grateful for financial support from a New Jersey Commission on Cancer Research Predoctoral Fellowship (MC), NIH grant R00-CA133181 (VK) and a Damon Runyon Clinical Investigator Award (VK).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Vazquez, Alexei
• Authors: Cicchini, M., Chakrabarti, R., Kongara, S., Price, S., Nahar, R., Lozy, F., Zhong, H., Vazquez, A., Kang, Y., and Karantza, V.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Autophagy
• Publisher: Taylor and Francis
• ISSN: 1554-8627
• ISSN (Online): 1554-8635
• Published Online: 30 October 2014
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Autophagy 10(11):2036-2052
• Publisher Policy: Reproduced under a Creative Commons license