The estrogen receptor α is the key regulator of the bifunctional role of FoxO3a transcription factor in breast cancer motility and invasiveness

Abstract

The role of the Forkhead box class O (FoxO)3a transcription factor in breast cancer migration and invasion is controversial. Here we show that FoxO3a overexpression decreases motility, invasiveness, and anchorage-independent growth in estrogen receptor α-positive (ERα+) cancer cells while eliciting opposite effects in ERα-silenced cells and in ERα-negative (ERα-) cell lines, demonstrating that the nuclear receptor represents a crucial switch in FoxO3a control of breast cancer cell aggressiveness. In ERα+ cells, FoxO3a-mediated events were paralleled by a significant induction of Caveolin-1 (Cav1), an essential constituent of caveolae negatively associated to tumor invasion and metastasis. Cav1 induction occurs at the transcriptional level through FoxO3a binding to a Forkhead responsive core sequence located at position -305/-299 of the Cav1 promoter. 17β-estradiol (E2) strongly emphasized FoxO3a effects on cell migration and invasion, while ERα and Cav1 silencing were able to reverse them, demonstrating that both proteins are pivotal mediators of these FoxO3a controlled processes. In vivo, an immunohistochemical analysis on tissue sections from patients with ERα+ or ERα- invasive breast cancers or in situ ductal carcinoma showed that nuclear FoxO3a inversely (ERα+) or directly (ERα-) correlated with the invasive phenotype of breast tumors. In conclusion, FoxO3a role in breast cancer motility and invasion depends on ERα status, disclosing a novel aspect of the well-established FoxO3a/ERα interplay. Therefore FoxO3a might become a pursuable target to be suitably exploited in combination therapies either in ERα+ or ERα- breast tumors.

Graded Inhibition of Oncogenic Ras-Signaling by Multivalent Ras-Binding Domains

“…This idea consists with breast cancer studies that have shown that FOXA1 functions as a tumor suppressor in ER-positive breast cancer cells (MCF-7) [28] but as a tumor activator in ER-negative breast cancer cells (MDA-MB-453) [12]. Furthermore, this idea of the effects of forkhead family members depending on ER expression is also consistent with the study that have shown the Forkhead box class o 3a transcription factor (FoxO3a) has inhibitory effects on motility and invasiveness of ER-positive breast cancer cells but inducing effects on motility and invasiveness of ERnegative breast cancer cells [35]. More comprehensive studies covering several EC cell lines in different cancer subtypes will be necessary to define the role of FOXA1 in EC development.…”

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

“…Conversely, FOXO3a nuclear localization is associated with good prognosis in luminal-like breast cancer (Habashy et al 2011). Moreover, exogenous expression of FOXO3a inhibits tumor growth in vitro and in vivo in breast cancer (Hu et al 2004;Yang et al 2008;Lin et al 2011;Sisci et al 2013).…”

Roles of the circular RNA circ-Foxo3 in breast cancer progression

“…4 In contrast, overexpression of Foxo3 decreases motility, invasiveness, and anchorage-independent growth. 5 Given that post-transcriptional repression of Foxo3 expression occurs through microRNA targeting as well as other transcription mechanisms, the Yang group made efforts in figuring out mechanisms by which circ-Foxo3 regulates Foxo3 expression. The circRNA, pseudogene, and linear mRNA shared common sites for binding to 8 microRNAs.…”