Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice

Jäger, Richard; Herzer, Ute; Schenkel, Johannes; Weiher, Hans

doi:10.1038/sj.onc.1201353

Cited by 144 publications

(81 citation statements)

References 32 publications

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“…Transgenic animals overexpressing Bcl-2-related proteins Transgene-enforced overexpression of members of the Bcl-2 family under the control of di erent promoters has revealed the striking capacity of Bcl-2 and Bcl-X L to confer apoptosis resistance to a number of di erent tissues including lymphocytes (McDonnell et al, 1989;Sentman et al, 1991;Strasser et al, 1991), spermatogonia (Furuchi et al, 1996), ovary follicles (Hsu et al, 1996), neurons , hepatocytes (Lacronique et al, 1996), retinal photoreceptors , mammary parenchyma (Jager et al, 1997), prostate epithelium (Zhang et al, 1997), keratinocytes (Pena et al, 1997), or lens cells (Fromm and Overbeek, 1997). Overexpression of Bcl-2 in lymphoid cells can cause the development of lymphomas.…”

Section: Biological E Ects Of Bcl-2-related Proteins In Vivomentioning

confidence: 99%

“…However, lymphomas only develop at an advanced age in an oligoclonal fashion, suggesting that additional mutations in (anti-) oncogenes have to occur to allow for tumor development (Cory, 1995). Accordingly, the simultaneously expression of other oncogenes such as c-myc substantially accelerates the development of lymphomas (Strasser et al, 1990(Strasser et al, , 1996 and mammary tumors induced by Bcl-2 expression (Jager et al, 1997). The cytoprotective e ect of Bcl-2 and Bcl-X L is rather broad.…”

Section: Biological E Ects Of Bcl-2-related Proteins In Vivomentioning

confidence: 99%

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Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

et al. 1998

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Bcl-2 is the prototype of a class of oncogenes which regulates apoptosis. Bcl-2-related gene products with either death-promoting and death-inhibitory activity are critically involved in numerous disease states and thus constitute prime targets for therapeutic interventions. The relative amount of death agonists and antagonists from the Bcl-2 family constitutes a regulatory rheostat whose function is determined, at least in part, by selective protein-protein interactions. Bcl-2 and its homologs insert into intracellular membranes including mitochondria, the endoplasmatic reticulum and the nuclear envelope. Many of the molecular genetic, ultrastructural, crystallographic and functional studies suggest that Bcl-2-related molecules exert their apoptosis-regulatory e ects via regulating mitochondrial alterations preceding the activation of apoptogenic proteases and nucleases. Via a direct e ect on mitochondrial membranes, Bcl-2 prevents all hallmarks of the early stage of apoptosis including disruption of the inner mitochondrial transmembrane potential and the release of apoptogenic protease activators from mitochondria. The mitochondrial permeability transition (PT) pore, also called mitochondrial megachannel or multiple conductance channel, is a multiprotein complex formed at the contact site between the mitochondrial inner and outer membranes, exactly at the same localization at which Bax, Bcl-2, and Bcl-X L are particularly abundant. The PT pore participates in the regulation of matrix Ca 2+ , pH, DC m , and volume and functions as a Ca 2+ -, voltage-, pH-, and redox-gated channel with several levels of conductance and little if any ion selectivity. Experiments involving the puri®ed PT pore complex indicate that Bax, Bcl-2, and Bcl-X L exert at least part of their apoptosis-regulatory function by facilitating (Bax) or inhibiting (Bcl-2, Bcl-X L ) PT pore opening. These ®ndings clarify the principal (but not exclusive) mechanism of Bcl-2-mediated cytoprotection.

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Section: Biological E Ects Of Bcl-2-related Proteins In Vivomentioning

confidence: 99%

Section: Biological E Ects Of Bcl-2-related Proteins In Vivomentioning

confidence: 99%

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

et al. 1998

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“…Mice that overexpress c-myc in the mammary gland are predisposed to develop mammary neoplasia (Stewart et al, 1984;Leder et al, 1986;Andres et al, 1988;Oncogene (2000) 19, 1092 ± 1096 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc *Correspondence: EP Sandgren Schoenenberger et al, 1988;Sandgren et al, 1995). Furthermore, as for TGFa, co-expression of c-myc with growth factors or other oncogenes increases the incidence of tumors and shortens their latency (Sinn et al, 1987;Andres et al, 1988;Sandgren et al, 1995;Amundadottir et al, 1995Amundadottir et al, , 1996Jager et al, 1997;McCormack et al, 1998).…”

Section: Tgfa and C-myc In Human Breast Cancermentioning

confidence: 99%

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

Rose-Hellekant

Sandgren

2000

Oncogene

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The growth factor transforming growth factor alpha (TGFa) and the nuclear transcription factor c-myc often are overexpressed by human breast cancer cells. To produce models of breast disease with these etiologies, mice were generated that carried TGF-a-or c-mycencoding transgenes. Transgene targeting employed the whey acidic protein (WAP) gene promoter, which is expressed in pregnant and lactating mammary epithelial cells. Non-virgin WAP-TGFa transgenic mice displayed accelerated mammary development during pregnancy, delayed post-parturient mammary involution, a progressive increase in the number of hyperplastic alveolar nodules (HANs), and development of mammary carcinoma with a mean latency of 9 months. Non-virgin WAP-c-myc transgenic mice displayed accelerated mammary gland development during pregnancy and development of mammary carcinomas with a latency of 8 months. Bitransgenic mice carrying both WAP-TGFa and WAPc-myc displayed a dramatic acceleration of tumor development. These models identify the overexpression of TGFa or c-myc as etiological factors in the development of mammary neoplasia and demonstrate the increased severity of disease when both molecular alterations are present in the same cell.

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“…[15][16][17] In these models, Myc-dependent mammary tumorigenesis is most likely limited by the induction of apoptosis, since tumors display increased levels of apoptosis and overexpression of Bcl -2 in the MMTV-Myc background accelerates tumor development. 18,19 Although several molecular factors involved in MYCinduced apoptosis have been identified, the mechanisms that enable cells to react to different levels of the transcription factor with the appropriate biological response had remained elusive. We have previously reported that MCF10A mammary epithelial cells engineered to express high levels of the 4-OHT inducible fusion protein MYC-ER undergo apoptosis.…”

Section: Introductionmentioning

confidence: 99%

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

et al. 2016

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Apoptosis caused by deregulated MYC expression is a prototype example of intrinsic tumor suppression. However, it is still unclear how supraphysiological MYC expression levels engage specific sets of target genes to promote apoptosis. Recently, we demonstrated that repression of SRF target genes by MYC/MIZ1 complexes limits AKT-dependent survival signaling and contributes to apoptosis induction. Here we report that supraphysiological levels of MYC repress gene sets that include markers of basal-like breast cancer cells, but not luminal cancer cells, in a MIZ1-dependent manner. Furthermore, repressed genes are part of a conserved gene signature characterizing the basal subpopulation of both murine and human mammary gland. These repressed genes play a role in epithelium and mammary gland development and overlap with genes mediating cell adhesion and extracellular matrix organization. Strikingly, acute activation of oncogenic MYC in basal mammary epithelial cells is sufficient to induce luminal cell identity markers. We propose that supraphysiological MYC expression impacts on mammary epithelial cell identity by repressing lineage-specific target genes. Such abrupt cell identity switch could interfere with adhesiondependent survival signaling and thus promote apoptosis in pre-malignant epithelial tissue.

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Overexpression of Bcl-2 inhibits alveolar cell apoptosis during involution and accelerates c-myc-induced tumorigenesis of the mammary gland in transgenic mice

Cited by 144 publications

References 32 publications

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins

Transforming growth factor alpha- and c-myc-induced mammary carcinogenesis in transgenic mice

MYC-induced apoptosis in mammary epithelial cells is associated with repression of lineage-specific gene signatures

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