Nuclear Mechanisms Involved in Endocrine Resistance

Abstract

Endocrine therapy is a standard treatment offered to patients with ERα (estrogen receptor α)-positive breast cancer. In endocrine therapy, ERα is either directly targeted by anti-estrogens or indirectly by aromatase inhibitors which cause estrogen deficiency. Resistance to these drugs (endocrine resistance) compromises the efficiency of this treatment and requires additional measures. Endocrine resistance is often caused by deregulation of the PI3K/AKT/mTOR pathway and/or cyclin-dependent kinase 4 and 6 activities allowing inhibitors of these factors to be used clinically to counteract endocrine resistance. The nuclear mechanisms involved in endocrine resistance are beginning to emerge. Exploring these mechanisms may reveal additional druggable targets, which could help to further improve patients' outcome in an endocrine resistance setting. This review intends to summarize our current knowledge on the nuclear mechanisms linked to endocrine resistance.

Keywords: cancer stem cells; chromatin accessibility; estrogen receptor; fulvestrant; tamoxifen; transcription factors; transcriptional reprogramming.

Figure 1

Mechanisms that induce ENDO-R by deregulation of the PI3K/AKT/mTOR and/or Ras/Raf/MEK/ERK1/2 pathways, two pathways that not only stimulate proliferation by raising cyclin D expression and thereby activating CDK4/6 but also promote survival. A common mechanism involves a higher activity of certain RTKs. This includes higher activities of Her proteins, induced by higher availability of ligands, such as EGF or HRG, or by gain-of-function mutation (Her2). FGFR1 is often amplified (amp) in ENDO-R and requires co-factors FGFR substrate 2 (FRS2) and phospholipase C-γ; (PLC-γ) to activate the two pathways. IR or IGF1R may contribute to ENDO-R if activated by insulin or IGFs. Higher IGF availability can be achieved by reduced expression of IGF binding proteins (IGFBPs). The expression of the IR/IGF1R co-factor insulin receptor substrate (IRS) may also play a role in ENDO-R. RTK-independent activation of PI3K/AKT/mTOR pathway is commonly caused by a gain-of-function mutation of the gene pik3ca coding for p110α, which together with p85α forms the PI3Kα complex. Dysfunction of PTEN, which prevents AKT activation by blocking the formation of phosphatidylinositol-3,4,5-trisphosphate (PIP₃) is another way by which this pathway can be upregulated. RTK-independent activation of the Ras/Raf/MEK/ERK1/2 pathway in ENDO-R include gain-of-function mutations in ras, raf or mek-encoding genes as well as dysfunction of NF1, an inhibitor of Ras. Arrows indicate positive, T-shaped symbols negative effects. A green or red star denotes a gain-of function or a loss-of-function mutation/deletion, respectively.

Figure 2

Nuclear proteins involved in ENDO-R. (A) Blockage of ERα function by FULV or TAM causes ARID1A to bind to FoxA1 leading to transcriptional inhibition of ERα-driven genes by recruitment of HDAC1. Dysfunctional ARID1A leads to higher abundance of acetylated histone 4 (acH4) and recruitment of BRD4, able to active transcription despite the presence of anti-estrogens. (B) ENDO-R often coincides with DNMT-mediated DNA methylation of ERα-driven genes at promoters and/or enhancers, resulting in blockage of ERα binding to these sites. (C) Acquisition of ENDO-R by transcriptionally re-programming cells. YB-1 suppresses ERα activity and upregulates the expression of Her2 and EGFR leading to a Her2-driven transcriptional pattern. Elf-5 inhibits the expression of ERα and FoxA1 and fosters a transcriptional pattern typically seen in basal-like breast cancer. (D) Hypoxia promotes ENDO-R by activating HIFs. FoxA1-regulated HIF-2α stimulates the transcription of EGFR and SNAT2, the latter being a transmembrane transporter and sensor of amino acids. Anti-estrogen resistant cells may use SNAT2-imported glutamine as a major carbohydrate source to maintain metabolism. (E) Independent of ERα, FoxA1 can stimulate the transcription of AGR2 and, in cooperation with GRHL2, the transcription of LYPDR3. AGR2 can cause the cyclin D1 synthesis to rise. FoxA1, GRHL2, LYPDR3 and AGR2 may act in concert to induce ENDO-R. (F) Members of the NFкB/Iк;B family may be involved in ENDO-R. NFкB supports ENDO-R by stimulating cyclin D1 expression and by inhibiting apoptosis. Bcl-3, whose expression in BCs is induced by MSC- and CAF-secreted factors, causes higher expression of proliferation-stimulatory c-Myc and anti-apoptotic stem cell factor Sox2 and blocks proliferation-inhibitory KLHL4. (G) Twist and ZEB1 can enhance CSC activity by inducing EMT. Additionally, Twist and ZEB1 can suppress ERα expression by recruiting DNMT to the esr1 promoter. ERα may limit CSC activity by suppressing the transcription of Notch4. One way involves induced expression of the transcriptional repressor DAXX followed by DNMT1-dependent methylation, another down-regulated abundance of Notch1-derived NICD1, a positive regulator of Notch4 transcription. Green and red ovals indicate proteins that promote or inhibit anti-estrogen resistance, respectively. Green arrows indicate a positive, red T-shaped symbols a blocking effect. Red circles denote CpG methylations.