Limits...
Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells.

Opyrchal M, Salisbury JL, Zhang S, McCubrey J, Hawse J, Goetz MP, Lomberk GA, Haddad T, Degnim A, Lange C, Ingle JN, Galanis E, D'Assoro AB - PLoS ONE (2014)

Bottom Line: Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation.This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis.We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.

ABSTRACT
Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

Show MeSH

Related in: MedlinePlus

Model of endocrine resistance and breast cancer progression.Aberrant activation of MAPK signaling stabilizes and activates Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through phosphorylation and activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4016211&req=5

pone-0096995-g005: Model of endocrine resistance and breast cancer progression.Aberrant activation of MAPK signaling stabilizes and activates Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through phosphorylation and activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression.

Mentions: Based on these findings and our published data [23], [25], we propose a novel model of endocrine resistance in initially ERα+ and hormone sensitive breast cancer cells: aberrant activation of MAPK signaling promotes phosphorylation and stabilization of Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression (Figure 5). Because our previous studies have demonstrated the causal role of aberrant Aurora-A kinase activity in the development of CD44+/CD24low/− cancer initiating cells [23], we speculate that Aurora-A/SMAD5 oncogenic axis may induce ERα down-regulation by promoting the clonal expansion of CD44+/CD24low/- cancer initiating cells that display low levels of ERα. Moreover, because Aurora-A is down-stream of MAPK, we believe that molecular targeting of Aurora-A in endocrine resistant breast cancer cells will be more effective than targeting MAPK pathway due to Aurora-A direct effects on the clonal expansion of CD44+/CD24low/−/ERαlow/− cancer initiating cells [23]. However, we don't exclude that patients with endocrine resistant breast tumors could benefit from the combination of MAPK and Aurora-A small molecule inhibitors.


Aurora-A mitotic kinase induces endocrine resistance through down-regulation of ERα expression in initially ERα+ breast cancer cells.

Opyrchal M, Salisbury JL, Zhang S, McCubrey J, Hawse J, Goetz MP, Lomberk GA, Haddad T, Degnim A, Lange C, Ingle JN, Galanis E, D'Assoro AB - PLoS ONE (2014)

Model of endocrine resistance and breast cancer progression.Aberrant activation of MAPK signaling stabilizes and activates Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through phosphorylation and activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016211&req=5

pone-0096995-g005: Model of endocrine resistance and breast cancer progression.Aberrant activation of MAPK signaling stabilizes and activates Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through phosphorylation and activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression.
Mentions: Based on these findings and our published data [23], [25], we propose a novel model of endocrine resistance in initially ERα+ and hormone sensitive breast cancer cells: aberrant activation of MAPK signaling promotes phosphorylation and stabilization of Aurora-A kinase that in turn induces down-regulation/loss of ERα expression through activation of SMAD5 nuclear signaling leading to endocrine resistance and tumor progression (Figure 5). Because our previous studies have demonstrated the causal role of aberrant Aurora-A kinase activity in the development of CD44+/CD24low/− cancer initiating cells [23], we speculate that Aurora-A/SMAD5 oncogenic axis may induce ERα down-regulation by promoting the clonal expansion of CD44+/CD24low/- cancer initiating cells that display low levels of ERα. Moreover, because Aurora-A is down-stream of MAPK, we believe that molecular targeting of Aurora-A in endocrine resistant breast cancer cells will be more effective than targeting MAPK pathway due to Aurora-A direct effects on the clonal expansion of CD44+/CD24low/−/ERαlow/− cancer initiating cells [23]. However, we don't exclude that patients with endocrine resistant breast tumors could benefit from the combination of MAPK and Aurora-A small molecule inhibitors.

Bottom Line: Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation.This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis.We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Mayo Clinic College Of Medicine, Rochester, Minnesota, United States of America.

ABSTRACT
Development of endocrine resistance during tumor progression represents a major challenge in the management of estrogen receptor alpha (ERα) positive breast tumors and is an area under intense investigation. Although the underlying mechanisms are still poorly understood, many studies point towards the 'cross-talk' between ERα and MAPK signaling pathways as a key oncogenic axis responsible for the development of estrogen-independent growth of breast cancer cells that are initially ERα+ and hormone sensitive. In this study we employed a metastatic breast cancer xenograft model harboring constitutive activation of Raf-1 oncogenic signaling to investigate the mechanistic linkage between aberrant MAPK activity and development of endocrine resistance through abrogation of the ERα signaling axis. We demonstrate for the first time the causal role of the Aurora-A mitotic kinase in the development of endocrine resistance through activation of SMAD5 nuclear signaling and down-regulation of ERα expression in initially ERα+ breast cancer cells. This contribution is highly significant for the treatment of endocrine refractory breast carcinomas, because it may lead to the development of novel molecular therapies targeting the Aurora-A/SMAD5 oncogenic axis. We postulate such therapy to result in the selective eradication of endocrine resistant ERαlow/- cancer cells from the bulk tumor with consequent benefits for breast cancer patients.

Show MeSH
Related in: MedlinePlus