Bax regulates c-Myc-induced mammary tumour apoptosis but not proliferation in MMTV-c-myc transgenic mice

Abstract

The expression of the proto-oncogene c-myc is frequently deregulated, via multiple mechanisms, in human breast cancers. Deregulated expression of c-myc contributes to mammary epithelial cell transformation and is causally involved in mammary tumorigenesis in MMTV-c-myc transgenic mice. c-Myc is known to promote cellular proliferation, apoptosis, genomic instability and tumorigenesis in several distinct tissues, both in vivo and in vitro. Expression of the proapoptotic regulatory gene bax is reduced or absent in human breast cancers, and c-Myc has been shown to regulate the expression of Bax, as well as cooperate with Bax in controlling apoptosis in a fibroblast model. Additionally, loss of bax reduces c-Myc-induced apoptosis in lymphoid cells and increases c-Myc-mediated lymphomagenesis in vivo. In order to assess whether loss of bax could influence c-Myc-induced apoptosis and tumorigenesis in the mammary gland in vivo, we generated MMTV-c-myc transgenic mice in which neither, one, or both wild-type alleles of bax were eliminated. Haploid loss of bax in MMTV-c-myc transgenic mice resulted in significantly reduced mammary tumour apoptosis. As anticipated for an apoptosis-regulatory gene, loss of the wild-type bax alleles did not significantly alter cellular proliferation in either mammary adenocarcinomas or dysplastic mammary tissues. However, in contrast to c-Myc-mediated lymphomagenesis, loss of one or both alleles of bax in MMTV-c-myc transgenic mice did not significantly enhance mammary tumorigenesis, despite evidence that haploid loss of bax might modestly increase mammary tumour multiplicity. Our results demonstrate that Bax contributes significantly to c-Myc-induced apoptosis in mammary tumours. In addition, they suggest that in contrast to c-Myc-induced lymphomagenesis, mammary tumorigenesis induced by deregulated c-myc expression requires some amount of Bax expression.

Specific Requirement for Bax, Not Bak, in Myc-induced Apoptosis and Tumor Suppression in Vivo

“…This is consistent with the established notion that apoptosis is the principal intrinsic mechanism limiting Myc-induced tumorigenesis (24). Recently, however, it was reported that although loss of Bax inhibits apoptosis in a classical, constitutive Myc-transgenic mouse model for mammary tumorigenesis (25), paradoxically such suppression of apoptosis did not appreciably promote Myc-induced tumorigenesis. This inconsistency may indicate that apoptosis suppresses tumorigenesis to different extents in differing tissues.…”

3D view to tumor suppression: lkb1, polarity and the arrest of oncogenic c-myc

“…On one hand, Bcl-2 reduces high apoptotic frequency observed in the c-Myc overexpressing mammary glands and accelerates c-Myc driven mammary tumorigenesis 60 but, on the other hand, loss of the pro-apoptotic (and Bcl-2 antagonizing) Bax also reduces apoptosis in the c-Myc induced mammary adenocarcinomas but it does not have any accelerating effect on tumorigenesis. 61 Thus, there are no definitive answers yet to the question whether apoptosis is a major or a minor roadblock hampering c-Myc-driven tumor development in the mammary gland.…”

c-Myc Blazing a Trail of Death: Coupling of the Mitochondrial and Death Receptor Apoptosis Pathways by c-Myc

“…For example, in the mouse mammary gland Bax-deficiency suppresses c-Myc-induced apoptosis without having effect on the c-Myc dependent tumorigenesis. 47 Furthermore, there are also tissues like skin keratinocytes, which are not prone to c-Myc-induced apoptosis and in these tissues inhibition of apoptosis may play lesser role in tumor progression. 48 The pro-apoptotic BH3-only member of Bcl-2 family, Bim (Box 2), has also been linked to c-Myc-dependent tumorigenesis.…”