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Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer.

Fox EM, Arteaga CL, Miller TW - Front Oncol (2012)

Bottom Line: In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy.PI3K activates several proteins which promote cell cycle progression and survival.In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, TN, USA.

ABSTRACT
Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

No MeSH data available.


Related in: MedlinePlus

Phosphatidylinositol 3-kinase is a central hub in signaling pathways required for estrogen-independent ER+ breast cancer cell growth. MCF-7/LTED cells transiently transfected with a siRNA library targeting 779 kinases were reseeded in hormone-depleted medium. Cell viability was measured 4–5 days later by Alamar blue assay. Median cell growth in four independent experiments was calculated for each kinase siRNA relative to non-silencing controls. Individual knockdown of 42 kinases inhibited MCF-7/LTED cell growth ≥33% (p ≤ 0.05) in at least three of four experiments (detailed in Fox et al., 2011). Ingenuity Pathways Analysis revealed that these 42 kinases map to several protein networks that overlap with PI3K signaling (red box, enlarged in bottom panel). Proteins involved in these networks are displayed as nodes. Solid lines indicate direct relationships between proteins, and dotted lines indicate indirect interactions. Green nodes represent the kinases identified in the screen, as well as others whose knockdown was predicted by the Ingenuity software to negatively affect cell growth. The various nodal shapes represent the functional class of the gene product.
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Figure 1: Phosphatidylinositol 3-kinase is a central hub in signaling pathways required for estrogen-independent ER+ breast cancer cell growth. MCF-7/LTED cells transiently transfected with a siRNA library targeting 779 kinases were reseeded in hormone-depleted medium. Cell viability was measured 4–5 days later by Alamar blue assay. Median cell growth in four independent experiments was calculated for each kinase siRNA relative to non-silencing controls. Individual knockdown of 42 kinases inhibited MCF-7/LTED cell growth ≥33% (p ≤ 0.05) in at least three of four experiments (detailed in Fox et al., 2011). Ingenuity Pathways Analysis revealed that these 42 kinases map to several protein networks that overlap with PI3K signaling (red box, enlarged in bottom panel). Proteins involved in these networks are displayed as nodes. Solid lines indicate direct relationships between proteins, and dotted lines indicate indirect interactions. Green nodes represent the kinases identified in the screen, as well as others whose knockdown was predicted by the Ingenuity software to negatively affect cell growth. The various nodal shapes represent the functional class of the gene product.

Mentions: In a siRNA screen against 779 kinases, we implicated insulin receptor (InsR) in the hormone-independent growth of MCF-7/LTED cells. InsR and its homolog IGF-1R dimerize and, upon ligand binding, potently activate PI3K. IGF-1R has also been shown to confer antiestrogen resistance in MCF-7 cells (Zhang et al., 2011). Treatment with the ATP-competitive IGF-1R/InsR inhibitor OSI-906 suppressed PI3K activation and hormone-independent ER+ cell growth (Fox et al., 2011). Network mapping of the 42 kinases individually implicated in MCF-7/LTED cell growth in this screen revealed that PI3K is a central hub in these signaling pathways (Figure 1). Interestingly, a recent study showed that in ER+ breast cancer cells treated with BEZ235 or with PI3K siRNA, exogenous 17β-estradiol rescued the cells from drug- and siRNA-induced apoptosis (Crowder et al., 2009; Sanchez et al., 2011). This suggests that in ER+ cancers treated with PI3K inhibitors, estrogen suppression should be maintained and, therefore, combined inhibition of both PI3K and ER may be more effective than single-agent therapies.


Abrogating endocrine resistance by targeting ERα and PI3K in breast cancer.

Fox EM, Arteaga CL, Miller TW - Front Oncol (2012)

Phosphatidylinositol 3-kinase is a central hub in signaling pathways required for estrogen-independent ER+ breast cancer cell growth. MCF-7/LTED cells transiently transfected with a siRNA library targeting 779 kinases were reseeded in hormone-depleted medium. Cell viability was measured 4–5 days later by Alamar blue assay. Median cell growth in four independent experiments was calculated for each kinase siRNA relative to non-silencing controls. Individual knockdown of 42 kinases inhibited MCF-7/LTED cell growth ≥33% (p ≤ 0.05) in at least three of four experiments (detailed in Fox et al., 2011). Ingenuity Pathways Analysis revealed that these 42 kinases map to several protein networks that overlap with PI3K signaling (red box, enlarged in bottom panel). Proteins involved in these networks are displayed as nodes. Solid lines indicate direct relationships between proteins, and dotted lines indicate indirect interactions. Green nodes represent the kinases identified in the screen, as well as others whose knockdown was predicted by the Ingenuity software to negatively affect cell growth. The various nodal shapes represent the functional class of the gene product.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472546&req=5

Figure 1: Phosphatidylinositol 3-kinase is a central hub in signaling pathways required for estrogen-independent ER+ breast cancer cell growth. MCF-7/LTED cells transiently transfected with a siRNA library targeting 779 kinases were reseeded in hormone-depleted medium. Cell viability was measured 4–5 days later by Alamar blue assay. Median cell growth in four independent experiments was calculated for each kinase siRNA relative to non-silencing controls. Individual knockdown of 42 kinases inhibited MCF-7/LTED cell growth ≥33% (p ≤ 0.05) in at least three of four experiments (detailed in Fox et al., 2011). Ingenuity Pathways Analysis revealed that these 42 kinases map to several protein networks that overlap with PI3K signaling (red box, enlarged in bottom panel). Proteins involved in these networks are displayed as nodes. Solid lines indicate direct relationships between proteins, and dotted lines indicate indirect interactions. Green nodes represent the kinases identified in the screen, as well as others whose knockdown was predicted by the Ingenuity software to negatively affect cell growth. The various nodal shapes represent the functional class of the gene product.
Mentions: In a siRNA screen against 779 kinases, we implicated insulin receptor (InsR) in the hormone-independent growth of MCF-7/LTED cells. InsR and its homolog IGF-1R dimerize and, upon ligand binding, potently activate PI3K. IGF-1R has also been shown to confer antiestrogen resistance in MCF-7 cells (Zhang et al., 2011). Treatment with the ATP-competitive IGF-1R/InsR inhibitor OSI-906 suppressed PI3K activation and hormone-independent ER+ cell growth (Fox et al., 2011). Network mapping of the 42 kinases individually implicated in MCF-7/LTED cell growth in this screen revealed that PI3K is a central hub in these signaling pathways (Figure 1). Interestingly, a recent study showed that in ER+ breast cancer cells treated with BEZ235 or with PI3K siRNA, exogenous 17β-estradiol rescued the cells from drug- and siRNA-induced apoptosis (Crowder et al., 2009; Sanchez et al., 2011). This suggests that in ER+ cancers treated with PI3K inhibitors, estrogen suppression should be maintained and, therefore, combined inhibition of both PI3K and ER may be more effective than single-agent therapies.

Bottom Line: In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy.PI3K activates several proteins which promote cell cycle progression and survival.In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Nashville, TN, USA.

ABSTRACT
Antiestrogen therapies targeting estrogen receptor α (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand-independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors.

No MeSH data available.


Related in: MedlinePlus