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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

Estrogen receptor inhibition with fulvestrant induces upregulation of PI3K signaling. Ovariectomized athymic mice were s.c. implanted with MCF-7 cells and a 10-day-release E2 pellet (0.12 mg). Twelve days later, mice were randomized to treatment with vehicle or fulvestrant (5 mg/week, s.c., clinical formulation). Tumors were harvested after 3–4 weeks of treatment. Tumor lysates were analyzed by immunoblotting using the indicated antibodies; each lane contains equal amount of protein from two to three tumors. Fulvestrant treatment decreased the levels of ER and ER-regulated genes products (PR, IGF-1R), but increased levels of P-AKT-T308 and P-AKT-S473, suggesting increased activation of PI3K. All lanes were from the same membrane.
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Figure 2: Estrogen receptor inhibition with fulvestrant induces upregulation of PI3K signaling. Ovariectomized athymic mice were s.c. implanted with MCF-7 cells and a 10-day-release E2 pellet (0.12 mg). Twelve days later, mice were randomized to treatment with vehicle or fulvestrant (5 mg/week, s.c., clinical formulation). Tumors were harvested after 3–4 weeks of treatment. Tumor lysates were analyzed by immunoblotting using the indicated antibodies; each lane contains equal amount of protein from two to three tumors. Fulvestrant treatment decreased the levels of ER and ER-regulated genes products (PR, IGF-1R), but increased levels of P-AKT-T308 and P-AKT-S473, suggesting increased activation of PI3K. All lanes were from the same membrane.

Mentions: Clinical evidence further indicates that PI3K pathway activation is associated with antiestrogen resistance. Patients bearing primary ER+ breast tumors which exhibit a protein expression/phosphorylation signature of PI3K activation, as determined using reverse-phase protein arrays (RPPA), have a shorter recurrence-free survival (Miller et al., 2010). RPPA analysis of ER+ primary breast tumors obtained from patients following 2–3 weeks of treatment with the AI letrozole showed that a protein signature of insulin signaling was associated with high post-AI tumor cell proliferation (Fox et al., 2011). Overexpression of HER2 or FGFR1, or loss of INPP4B, molecular lesions which activate the PI3K pathway, also confer antiestrogen resistance in patients with ER+ breast cancer (Arpino et al., 2004; De Laurentiis et al., 2005; Ellis et al., 2006; Gewinner et al., 2009; Turner et al., 2010). Also noteworthy is the inverse correlation between levels of PI3K activation and ER protein in human tumors. This ER/PI3K balance can be shifted using PI3K and ER inhibitors in preclinical models (Figure 2; Creighton et al., 2010; Miller et al., 2010), suggesting that cells may defer to the other pathway when one is inhibited.


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

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

Estrogen receptor inhibition with fulvestrant induces upregulation of PI3K signaling. Ovariectomized athymic mice were s.c. implanted with MCF-7 cells and a 10-day-release E2 pellet (0.12 mg). Twelve days later, mice were randomized to treatment with vehicle or fulvestrant (5 mg/week, s.c., clinical formulation). Tumors were harvested after 3–4 weeks of treatment. Tumor lysates were analyzed by immunoblotting using the indicated antibodies; each lane contains equal amount of protein from two to three tumors. Fulvestrant treatment decreased the levels of ER and ER-regulated genes products (PR, IGF-1R), but increased levels of P-AKT-T308 and P-AKT-S473, suggesting increased activation of PI3K. All lanes were from the same membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Estrogen receptor inhibition with fulvestrant induces upregulation of PI3K signaling. Ovariectomized athymic mice were s.c. implanted with MCF-7 cells and a 10-day-release E2 pellet (0.12 mg). Twelve days later, mice were randomized to treatment with vehicle or fulvestrant (5 mg/week, s.c., clinical formulation). Tumors were harvested after 3–4 weeks of treatment. Tumor lysates were analyzed by immunoblotting using the indicated antibodies; each lane contains equal amount of protein from two to three tumors. Fulvestrant treatment decreased the levels of ER and ER-regulated genes products (PR, IGF-1R), but increased levels of P-AKT-T308 and P-AKT-S473, suggesting increased activation of PI3K. All lanes were from the same membrane.
Mentions: Clinical evidence further indicates that PI3K pathway activation is associated with antiestrogen resistance. Patients bearing primary ER+ breast tumors which exhibit a protein expression/phosphorylation signature of PI3K activation, as determined using reverse-phase protein arrays (RPPA), have a shorter recurrence-free survival (Miller et al., 2010). RPPA analysis of ER+ primary breast tumors obtained from patients following 2–3 weeks of treatment with the AI letrozole showed that a protein signature of insulin signaling was associated with high post-AI tumor cell proliferation (Fox et al., 2011). Overexpression of HER2 or FGFR1, or loss of INPP4B, molecular lesions which activate the PI3K pathway, also confer antiestrogen resistance in patients with ER+ breast cancer (Arpino et al., 2004; De Laurentiis et al., 2005; Ellis et al., 2006; Gewinner et al., 2009; Turner et al., 2010). Also noteworthy is the inverse correlation between levels of PI3K activation and ER protein in human tumors. This ER/PI3K balance can be shifted using PI3K and ER inhibitors in preclinical models (Figure 2; Creighton et al., 2010; Miller et al., 2010), suggesting that cells may defer to the other pathway when one is inhibited.

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