Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells

Abstract

Fatty acid synthase (FASN), the key enzyme for endogenous synthesis of fatty acids, is overexpressed and hyperactivated in a biologically aggressive subset of sex steroid-related tumors, including breast carcinomas. Using pharmacological and genetic approaches, we assessed the molecular relationship between FASN signaling and estrogen receptor alpha (ERα) signaling in breast cancer. The small compound C75, a synthetic slow-binding inhibitor of FASN activity, induced a dramatic augmentation of estradiol (E2)-stimulated, ERα-driven transcription. FASN and ERα were both necessary for the synergistic activation of ERα transcriptional activity that occurred following co-exposure to C75 and E2: first, knockdown of FASN expression using RNAi (RNA interference) drastically lowered (>100 fold) the amount of E2 required for optimal activation of ERα-mediated transcriptional activity; second, FASN blockade synergistically increased E2-stimulated ERα-mediated transcriptional activity in ERα-negative breast cancer cells stably transfected with ERα, but not in ERα-negative parental cells. Non-genomic, E2-regulated cross-talk between the ERα and MAPK pathways participated in these phenomena. Thus, treatment with the pure antiestrogen ICI 182 780 or the potent and specific inhibitor of MEK/ERK, U0126, was sufficient to abolish the synergistic nature of the interaction between FASN blockade and E2-stimulated ERα transactivation. FASN inhibition suppressed E2-stimulated breast cancer cell proliferation and anchorage-independent colony formation while promoting the reduction of ERα protein. FASN blockade resulted in the increased expression and nuclear accumulation of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27Kip1, two critical mediators of the therapeutic effects of antiestrogen in breast cancer, while inactivating AKT, a key mediator of E2-promoted anchorage-independent growth. The ability of FASN to regulate E2/ERα signaling may represent a promising strategy for anticancer treatment involving a new generation of FASN inhibitors.

Reprogramming of fatty acid metabolism in cancer

“…In these models, both genetic and pharmacological inhibition of FASN hypersensitises ERα to oestrogen-dependent transactivation, thus leading to a synergistic induction of both oestrogen receptor element (ERE) transcriptional activity and mitogen-activated protein kinase (MAPK)-ERK signalling. 122 Surprisingly, oestrogen stimulation following FASN inhibition has significant cytotoxic and cytostatic effects, despite activation of the seemingly protumorigenic aforementioned processes. 122 Whilst this may seem paradoxical at first, these findings highlight a novel role for FASN in modulating the thresholds required for triggering hormone receptor signalling, and consequently regulating the balance between the opposing pro-tumorigenic and anti-proliferative effects of ERα stimulation.…”

“…122 Surprisingly, oestrogen stimulation following FASN inhibition has significant cytotoxic and cytostatic effects, despite activation of the seemingly protumorigenic aforementioned processes. 122 Whilst this may seem paradoxical at first, these findings highlight a novel role for FASN in modulating the thresholds required for triggering hormone receptor signalling, and consequently regulating the balance between the opposing pro-tumorigenic and anti-proliferative effects of ERα stimulation. For instance, although oestrogen signalling contributes to the upregulation of genes involved in proliferation, invasion and metastasissuch as Twist and matrix metalloproteinases 2/9 (MMP2/9) -FASN blockade leads to the nuclear accumulation of the oestradiol (E 2 ) targets p21 WAF/CIP1 and p27 Kip1 , culminating in cell-cycle inhibition and induction of cytostatic and cytotoxic effects in response to E 2 exposure.…”

“…For instance, although oestrogen signalling contributes to the upregulation of genes involved in proliferation, invasion and metastasissuch as Twist and matrix metalloproteinases 2/9 (MMP2/9) -FASN blockade leads to the nuclear accumulation of the oestradiol (E 2 ) targets p21 WAF/CIP1 and p27 Kip1 , culminating in cell-cycle inhibition and induction of cytostatic and cytotoxic effects in response to E 2 exposure. 122,123 Moreover, it is interesting to note that while E 2 hyperactivates MAPK-ERK signalling following FASN inhibition, PI3K-AKT activity is attenuated. 122 Indeed, there exists significant crosstalk between MAPK-ERK and PI3K-AKT signalling encompassing both positiveand negative-feedback loops, and this may explain at least one of the mechanisms responsible for the observed effects of FASN blockade and E 2 exposure.…”

“…122,123 Moreover, it is interesting to note that while E 2 hyperactivates MAPK-ERK signalling following FASN inhibition, PI3K-AKT activity is attenuated. 122 Indeed, there exists significant crosstalk between MAPK-ERK and PI3K-AKT signalling encompassing both positiveand negative-feedback loops, and this may explain at least one of the mechanisms responsible for the observed effects of FASN blockade and E 2 exposure. 124 In terms of cross-inhibition, ERK has been shown to phosphorylate the scaffold protein GRB2associated-binding protein 1 (GAB1), thus compromising the recruitment of PI3K to the plasma membrane and downstream activation of AKT.…”

SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract

“…FASN activity and AKT1 activation are modulated in a coregulatory pathway-FASN regulates AKT1 and activated AKT1 regulates FASN. AKT1 activation protects cells against FASN inhibition-induced cell death by increasing transcription of FASN [43,44]. Our data show that Vermentino leaf extract triggered activation of AKT1 via phosphorylation as well as increased FASN mRNA levels in MCF-7 and SKBR-3 cells.…”