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BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

Oncogene volume 29, pages 527–538 (2010)Cite this article

Abstract

Although the multi-functional, prosurvival protein, Bcl-2-associated anthanogene 1 (BAG-1) is frequently overexpressed in breast cancers, its role in the development or maintenance of the malignant state remains unclear. Here, we have used the established MCF-10A 3-dimensional (3D) model of mammary morphogenesis as a biologically relevant system to determine how BAG-1 expression may influence the development of breast cancer. When cultured in 3D, MCF-10A cells undergo a highly regulated morphogenic program leading to the development of polarized acinar structures containing a central, hollow lumen formed, in part, through the induction of BIM-dependent apoptosis. BAG-1 overexpression resulted in an attenuation of this normal apoptotic program characterized by a significantly increased number of acini with filled lumens—a phenotype commonly observed in ductal carcinoma in situ. BAG-1's effects were associated with an activation of RAF-1—a known binding partner of BAG-1, enhanced signaling through the MAP kinase pathway and a decrease in BIM expression. Reversal of the BAG-1-associated survival phenotype by the mitogen-activated kinase/ERK kinase inhibitor, U0126, implicates the RAF-1–extracellular signal-regulated kinase signaling pathway as a major mediator of BAG-1's effects in this model. As BAG-1 expression is often elevated in preinvasive breast cancers, these findings support a possible role for BAG-1 as an early contributor to the malignant process in the breast.

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Abbreviations

BAG-1:

Bcl-2-associated anthanogene

ERK:

extracellular signal regulated kinase

MEK:

mitogen-activated kinase/ERK kinase

ER:

estrogen receptor

DCIS:

ductal carcinoma in situ

3D:

three-dimensional

DAPI:

4′,6-diamidino-2-phenylindole

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Acknowledgements

We gratefully acknowledge the assistance of Drs Will Hughes and James Burchfield (Garvan Institute) with confocal microscopy, and Professor Graham Packham (University of Southampton) for useful discussions. This study was supported by Cancer Institute NSW Postgraduate Scholarship and Australian Postgraduate Award (LRA); Cancer Institute NSW Career Development and Support Fellowship (AJB); National Health and Medical Research Council (Australia) Program Grant 535903; RT Hall Trust.

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  1. Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

    L R Anderson, R L Sutherland & A J Butt

  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    R L Sutherland & A J Butt

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Correspondence to A J Butt.

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Anderson, L., Sutherland, R. & Butt, A. BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation. Oncogene 29, 527–538 (2010). https://doi.org/10.1038/onc.2009.362

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