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cIAP2 Is an Independent Signaling and Survival Factor during Mammary Lactational Involution and Tumorigenesis

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Abstract

Cellular inhibitor of apoptosis proteins-1 and -2 (cIAP1/2) are integral to regulation of apoptosis and signaling by the tumor necrosis factor (TNF) and related family of receptors. The expression of cIAP2 in tissues is typically low and considered functionally redundant with cIAP1, however cIAP2 can be activated by a variety of cellular stresses. Members of the TNFR family and their ligands have essential roles in mammary gland biology. We have found that cIAP2−/− virgin mammary glands have reduced ductal branching and delayed lobuloalveogenesis in early pregnancy. Post-lactational involution involves two phases where the first phase is reversible and is mediated, in part, by TNFR family ligands. In cIAP2−/− mice mammary glands appeared engorged at mid-lactation accompanied by enhanced autophagic flux and decreased cIAP1 protein expression. Severely stretched myoepithelium was associated with BIM-EL expression and other indicators of anoikis. Within 24 h after forced or natural weaning, cIAP2−/− glands had nearly completed involution. The TNF-related weak inducer of apoptosis (Tweak) which results in degradation of cIAP1 through its receptor, Fn14, began to increase in late lactation and was significantly increased in cIAP2−/− relative to WT mice by 12 h post weaning accompanied by decreased cIAP1 protein expression. Carcinogen/progesterone-induced mammary tumorigenesis was significantly delayed in cIAP2−/− mice and tumors contained high numbers of apoptotic cells. We conclude that cIAP2 has a critical role in the mammary gland wherein it prevents rapid involution induced by milk stasis-induced stress associated with Tweak activation and contributes to the survival of mammary tumor cells.

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Fig. 1: Expression of cIAP1/2 and histological comparison between cIAP2 null and wild-type mammary glands during development.
Fig. 2: Histological evidence of precocious involution in cIAP2−/− mammary glands.
Fig. 3: Absence of cIAP2 results in hyperactivation of Tweak expression and amplified death signaling in vivo.
Fig. 4: Evidence for autophagy and anoikis-associated cell death signaling prior to weaning in cIAP2−/− mammary tissue.
Fig. 5: Absence of cIAP2 results in accelerated mammary involution associated with precocious apoptosis.
Fig. 6: Mice lacking cIAP2 develop tumors with long relative latency.
Fig. 7: Proposed roles of cIAP2 in the mammary gland.

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Acknowledgements

We thank Dr. Robert Korneluk for the generous gift of cIAP2-null mice and Drs. Eric Lacasse and Paul Hamel for helpful discussion. We thank Min Ying Niu for expert technical assistance. This work was supported by grants from the Canadian Institutes of Health Research grant FRN 79304 and the Canadian Breast Cancer Foundation, Ontario to M.A.C.P.

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  1. Rosanna Lau

    Present address: Department of Pathology, The UT M.D. Anderson Cancer Center, Houston, TX, USA

  2. David Carr and Rosanna Lau contributed equally to this work.

Authors and Affiliations

  1. Breast Cancer Research Lab, Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada

    David Carr, Rosanna Lau, Alexandra D. Hnatykiw, Gwendoline C. D. Ward, Miguel A. Cabrita & M. A. Christine Pratt

  2. Ottawa Hospital Regional Cancer Centre, Centre for Cancer Therapeutics, 3rd floor, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada

    Manijeh Daneshmand

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Carr, D., Lau, R., Hnatykiw, A.D. et al. cIAP2 Is an Independent Signaling and Survival Factor during Mammary Lactational Involution and Tumorigenesis. J Mammary Gland Biol Neoplasia 23, 109–123 (2018). https://doi.org/10.1007/s10911-018-9398-y

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