CUEDC1 is a primary target of ERα essential for the growth of breast cancer cells

Abstract

Breast cancer is the most prevalent type of malignancy in women with ∼1.7 million new cases diagnosed annually, of which the majority express ERα (ESR1), a ligand-dependent transcription factor. Genome-wide chromatin binding maps suggest that ERα may control the expression of thousands of genes, posing a great challenge in identifying functional targets. Recently, we developed a CRISPR-Cas9 functional genetic screening approach to identify enhancers required for ERα-positive breast cancer cell proliferation. We validated several candidates, including CUTE, a putative ERα-responsive enhancer located in the first intron of CUEDC1 (CUE-domain containing protein). Here, we show that CUTE controls CUEDC1 expression, and that this interaction is essential for ERα-mediated cell proliferation. Moreover, ectopic expression of CUEDC1, but not a CUE-domain mutant, rescues the defects in CUTE activity. Finally, CUEDC1 expression correlates positively with ERα in breast cancer. Thus, CUEDC1 is a functional target gene of ERα and is required for breast cancer cell proliferation.

CUEDC1 inhibits epithelial-mesenchymal transition via the TβRI/Smad signaling pathway and suppresses tumor progression in non-small cell lung cancer

“…Our conclusion that CUEDC1 was a tumor-suppressive gene appears to conflict with the observations in breast and cervical cancer [ 20 , 21 ]. In breast cancer, CUEDC1 as a cancer-promoting gene was essential for the ERα-mediated stimulation of cancer cell proliferation [ 20 ]. Such an inconsistency may be due to the differences in the tissue specificity of different type cancers.…”

“…To date, little is known regarding CUEDC1, although CUEDC1 was found to be remarkably lower in a group with preeclampsia compared with the normal pregnancy group [ 19 ]. Lopes et al reported that CUEDC1 is a functional target of ERα and is required for breast cancer cell proliferation [ 20 ]. In early-stage cervical cancer, CUEDC1 was elevated in metastasized tumors compared with non-metastasized tumors [ 21 ].…”

A CRISPR-Cas9 screen identifies essential CTCF anchor sites for estrogen receptor-driven breast cancer cell proliferation

“…This pipeline resulted in 668 CBEs to which we generated 1,709 targeting sgRNA vectors. We also added 82 non-targeting sgRNA vectors (negative controls) and an sgRNA vector targeting ERα-bound enhancer (ERα 1830 ) that we previously showed its requirement for mediating ERα-driven cell proliferation (positive control (40,58)). A lentiviral library was generated and named as CRISPR-CTCF ERα .…”

ELF5 modulates the estrogen receptor cistrome in breast cancer

“…For example, CD36 increased proliferation and migration of breast cancer cells and antagonised tamoxifen effects [40]. CUEDC1 is a transcriptional target of ER regulated via the associated CUTE enhancer discovered by CRISPR screening [51] and its product is essential for ER-driven MCF-7 cell proliferation [41]. LAMP3 is a regulator of autophagy that is induced by tamoxifen and causes insensitivity to this drug.…”

“…Six genes, (CD36 [40], CUEDC1 [41], LAMP3 [42], SDCBP [43], LTBP2 [44], PIP [45]), of the set of 26 differentially expressed genes with enriched or depleted binding of FOXA1 or ER in response to induction of ELF5, are implicated endocrine resistance, and nearly all genes in this set appear in one or more gene sets derived from estrogen action, breast cancer subtype or endocrine resistance. Fig 4C shows ChIP-seq and RNA-seq results for one example, PIP.…”