Abstract
Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.
Highlights
Materials and MethodsEndometrial cancer (EC) is the most common gynecologic malignancy in the USA, with approximately 60,000 new diagnosed cases per year [1]
To determine whether the observed effects of short-term MET on tumor samples resulted from its direct actions on tumor epithelial cells, the human Ishikawa cell line, which was derived from the epithelial component of a well-differentiated endometrial adenocarcinoma [24], was treated with MET, and the parameters measured in vivo were evaluated in vitro
We examined whether MET affects the functional linkage between Krüppel-like factor 9 (KLF9), Krüppel-like factor 4 (KLF4), and progesterone receptor (PGR) in endometrial cancer (EC) cells transiently transfected with small interfering RNAs (siRNAs) directed against KLF9 and in parallel with control siRNAs
Summary
Materials and MethodsEndometrial cancer (EC) is the most common gynecologic malignancy in the USA, with approximately 60,000 new diagnosed cases per year [1]. The present study examined the short-term effects of MET on tissue proliferation, apoptosis, and expression of estrogen receptor-α (ERα), progesterone receptor (PGR), specificity protein (Sp)–related transcription factor Krüppel-like factor 9 (KLF9) and tumor suppressor phosphatase and tensin homolog (PTEN) in endometrial tumors of non-diabetic obese women with EC.
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