The emerging role of Krüppel-like factors in endocrine-responsive cancers of female reproductive tissues

Abstract

Krüppel-like factors (KLFs), of which there are currently 17 known protein members, belong to the specificity protein (Sp) family of transcription factors and are characterized by the presence of Cys 2 /His 2 zinc finger motifs in their carboxyterminal domains that confer preferential binding to GC/GTrich sequences in gene promoter and enhancer regions. While previously regarded to simply function as silencers of Sp1 transactivity, many KLFs are now shown to be relevant to human cancers by their newly identified abilities to mediate crosstalk with signaling pathways involved in the control of cell proliferation, apoptosis, migration, and differentiation. Several KLFs act as tumor suppressors and/or oncogenes under distinct cellular contexts, underscoring their prognostic potential for cancer survival and outcome. Recent studies suggest that a number of KLFs can influence steroid hormone signaling through transcriptional networks involving steroid hormone receptors and members of the nuclear receptor family of transcription factors. Since inappropriate sensitivity or resistance to steroid hormone actions underlies endocrinerelated malignancies, we consider the intriguing possibility that dysregulation of expression and/or activity of KLF members is linked to the pathogenesis of endometrial and breast cancers. In this review, we focus on recently described mechanisms of actions of several KLFs (KLF4, KLF5, KLF6, and KLF9) in cancers of the mammary gland and uterus. We suggest that understanding the mode of actions of KLFs and their functional networks may lead to the development of novel therapeutics to improve current prospects for cancer prevention and cure.

Endometrial miR-200c is Altered During Transformation into Cancerous States and Targets the Expression of ZEBs, VEGFA, FLT1, IKKβ, KLF9, and FBLN5

“…56,61,62 We found that KLF9 is a direct target of miR200c, and since gain of function of miR-200c increased the rate of Ishikawa cell proliferation, we speculate that this increase in the cell proliferation is mediated through KLF9 repression, similar to the results reported earlier using KLF9 siRNA approach. 62 Since several other miRNAs are predicted to target the expression of these genes, further investigation is needed for establishing the complex regulatory interaction among these genes and miRNAs that target their expression.…”

“…Although our finding with miR-200c regulation of KLF9 is the first of such validation, others reported VEGFA, FLT1, ETS1, SUZ12, PDGF, TGF-b2, and conexin43, as well as Notch pathway components, such as Jagged1 (JAG1) and mastermind-like [24][25][26][27][28][29][30]41 Because of the lack of adequate endometrial biopsies and endometrial cancer tissues, we could not determine the coexpression of VEGFA, FLT1, IKKb, and KLF9 in the same tissues; however, several studies reported their expression in human endometrium with altered or aberrant expression in endometriosis and endometrial cancer. [48][49][50][51][52][53][54][55][56][57][58] The biological significance of VEGFA and their receptors (FLT1 and VEGFR1), in various activities, including angiogenesis, is well established, including in normal endometrium throughout the menstrual cycle, dysfunctional uterine bleeding, and endometrial repair and endometrial cancer. 53,54,57 Additionally, IKKb by serving as a cofactor for activation of NFkb pathway plays a key role in regulating the expression of many proinflammatory mediators, including interleukin 8.…”

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor β-KLF5 Pathway

“…We previously reported that prostate tumor growth is regulated through the ER␤-dependent nonclassical pathway with Krüppel-like zinc finger transcription factor 5 (KLF5) (25). KLF5 (also known as BTEB2 or IKLF) is a transcription factor that possesses both tumor-suppressing and tumor-promoting activities (26)(27)(28). Analysis of the associated pathway revealed that in the absence of E2, ER␤ induces the KLF5-mediated expression of FOXO1 and increases anoikis, thereby suppressing prostate tumor growth in mouse xenograft models.…”

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

“…In mammals they constitute a large family of factors containing at least seventeen members that bind to a CACCC or CGCCC DNA motif (14,15). KLF's have pleiotropic functions that both enhance and inhibit transcription (16), and through competition for binding to their target sequences, they can mutually antagonize each other (15,17). They have a wide range of functions in regulating cell cycle, apoptosis, and differentiation (15).…”

“…KLFs affect expression of proproliferative genes such as E, D and A type cyclins. They also regulate several antiproliferative genes, for example p53 and E cadherin (17). KLF9 expressed in the uterus has a role in reproduction; its loss results in a modest reduction in fertility in mice caused by an implantation failure secondary to the attenuation and delay of cell proliferation in the luminal and glandular epithelium in response to E 2 (18)(19)(20).…”