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Cutting the brakes and flooring the gas: how TMEPAI turns TGF-β into a tumor promoter.

Cichon MA, Radisky DC - Genes Cancer (2014)

Bottom Line: In normal or nonmalignant cells, TGF-β inhibits cellular proliferation through activation of the SMAD-dependent canonical signaling pathway.Recent findings demonstrate that the protein TMEPAI1 can block the cytostatic effects of the canonical TGF-β signaling pathway, while activating cellular proliferation through the noncanonical, SMAD-independent TGF-β signaling pathway.As TMEPAI1 shows increased expression in the poor prognosis basal and HER2 intrinsic subtypes of breast cancer, these findings point to a new avenue of targeted therapy with considerable therapeutic potential.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic Cancer Center, Jacksonville, FL, USA.

ABSTRACT
In normal or nonmalignant cells, TGF-β inhibits cellular proliferation through activation of the SMAD-dependent canonical signaling pathway. Recent findings demonstrate that the protein TMEPAI1 can block the cytostatic effects of the canonical TGF-β signaling pathway, while activating cellular proliferation through the noncanonical, SMAD-independent TGF-β signaling pathway. As TMEPAI1 shows increased expression in the poor prognosis basal and HER2 intrinsic subtypes of breast cancer, these findings point to a new avenue of targeted therapy with considerable therapeutic potential.

No MeSH data available.


Related in: MedlinePlus

TMEPAI expression levels are prognostic for relapse-free survival in HER2+ breast cancerHER2-expressing intrinsic subtype breast cancer patients, divided into three groups based upon TMEPAI (PMEPA1) transcript levels (grey trace, low expression, n=40 patients; red trace, medium expression, n=42 patients; blue trace, high expression, n=40 patients) showed significant differences (p=0.00095) in relapse-free survival (RFS). Meta-analysis performed using the GOBO server (http://co.bmc.lu.se/gobo/gsa.pl).
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Figure 2: TMEPAI expression levels are prognostic for relapse-free survival in HER2+ breast cancerHER2-expressing intrinsic subtype breast cancer patients, divided into three groups based upon TMEPAI (PMEPA1) transcript levels (grey trace, low expression, n=40 patients; red trace, medium expression, n=42 patients; blue trace, high expression, n=40 patients) showed significant differences (p=0.00095) in relapse-free survival (RFS). Meta-analysis performed using the GOBO server (http://co.bmc.lu.se/gobo/gsa.pl).

Mentions: These studies suggest that inhibition of TMEPAI may be a useful therapeutic approach for TNBC patients, although methods to accomplish this are unclear. It may be that identification and development of novel reagents to disrupt the interaction of TMEPAI with SMADs could be used in combination with PI3K- or Akt-targeting therapeutics currently in clinical trials to reactivate the cytostatic capability of TGF-β. It may be that other breast cancer subtypes could benefit from this approach as well. Interrogating a large meta-analysis of published breast cancer microarray datasets [11] in which cancers could be segregated according to PAM50-derived intrinsic subtypes [12], revealed that increased expression of TMEPAI in HER2-expressing breast cancers was associated with significantly poorer patient prognosis (Fig. 2). Strikingly, HER2 has also been shown to potentiate the protumorigenic effects of TGF-β in preclinical models [13]. Given that patients with HER2-expressing breast cancers also have a poorer relative prognosis, particularly when their cancers are initially resistant or acquire resistance to the HER2 targeting agent trastuzumab [14], investigation of the potential benefit for blocking the protumorigenic effects of TMEPAI in this cancer subtype may also be warranted.


Cutting the brakes and flooring the gas: how TMEPAI turns TGF-β into a tumor promoter.

Cichon MA, Radisky DC - Genes Cancer (2014)

TMEPAI expression levels are prognostic for relapse-free survival in HER2+ breast cancerHER2-expressing intrinsic subtype breast cancer patients, divided into three groups based upon TMEPAI (PMEPA1) transcript levels (grey trace, low expression, n=40 patients; red trace, medium expression, n=42 patients; blue trace, high expression, n=40 patients) showed significant differences (p=0.00095) in relapse-free survival (RFS). Meta-analysis performed using the GOBO server (http://co.bmc.lu.se/gobo/gsa.pl).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209605&req=5

Figure 2: TMEPAI expression levels are prognostic for relapse-free survival in HER2+ breast cancerHER2-expressing intrinsic subtype breast cancer patients, divided into three groups based upon TMEPAI (PMEPA1) transcript levels (grey trace, low expression, n=40 patients; red trace, medium expression, n=42 patients; blue trace, high expression, n=40 patients) showed significant differences (p=0.00095) in relapse-free survival (RFS). Meta-analysis performed using the GOBO server (http://co.bmc.lu.se/gobo/gsa.pl).
Mentions: These studies suggest that inhibition of TMEPAI may be a useful therapeutic approach for TNBC patients, although methods to accomplish this are unclear. It may be that identification and development of novel reagents to disrupt the interaction of TMEPAI with SMADs could be used in combination with PI3K- or Akt-targeting therapeutics currently in clinical trials to reactivate the cytostatic capability of TGF-β. It may be that other breast cancer subtypes could benefit from this approach as well. Interrogating a large meta-analysis of published breast cancer microarray datasets [11] in which cancers could be segregated according to PAM50-derived intrinsic subtypes [12], revealed that increased expression of TMEPAI in HER2-expressing breast cancers was associated with significantly poorer patient prognosis (Fig. 2). Strikingly, HER2 has also been shown to potentiate the protumorigenic effects of TGF-β in preclinical models [13]. Given that patients with HER2-expressing breast cancers also have a poorer relative prognosis, particularly when their cancers are initially resistant or acquire resistance to the HER2 targeting agent trastuzumab [14], investigation of the potential benefit for blocking the protumorigenic effects of TMEPAI in this cancer subtype may also be warranted.

Bottom Line: In normal or nonmalignant cells, TGF-β inhibits cellular proliferation through activation of the SMAD-dependent canonical signaling pathway.Recent findings demonstrate that the protein TMEPAI1 can block the cytostatic effects of the canonical TGF-β signaling pathway, while activating cellular proliferation through the noncanonical, SMAD-independent TGF-β signaling pathway.As TMEPAI1 shows increased expression in the poor prognosis basal and HER2 intrinsic subtypes of breast cancer, these findings point to a new avenue of targeted therapy with considerable therapeutic potential.

View Article: PubMed Central - PubMed

Affiliation: Mayo Clinic Cancer Center, Jacksonville, FL, USA.

ABSTRACT
In normal or nonmalignant cells, TGF-β inhibits cellular proliferation through activation of the SMAD-dependent canonical signaling pathway. Recent findings demonstrate that the protein TMEPAI1 can block the cytostatic effects of the canonical TGF-β signaling pathway, while activating cellular proliferation through the noncanonical, SMAD-independent TGF-β signaling pathway. As TMEPAI1 shows increased expression in the poor prognosis basal and HER2 intrinsic subtypes of breast cancer, these findings point to a new avenue of targeted therapy with considerable therapeutic potential.

No MeSH data available.


Related in: MedlinePlus