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Epidemiological and clinical evidence have extensively documented the role of obesity in the development of endometrial cancer. However, the effect of fatty acids on cell growth in endometrial cancer has not been widely studied. Here, we reported that palmitic acid significantly inhibited cell proliferation of endometrial cancer cells and primary cultures of endometrial cancer and reduced tumor growth in a transgenic mouse model of endometrial cancer, in parallel with increased cellular stress and apoptosis and decreased cellular adhesion and invasion. Inhibition of cellular stress by N-acetyl-L-cysteine effectively reversed the effects of palmitic acid on cell proliferation, apoptosis, and invasive capacity in endometrial cancer cells. Palmitic acid increased the intracellular formation of lipid droplets in a time- and dose-dependent manner. Depletion of lipid droplets by blocking DGAT1 and DGAT2 effectively increased the ability of palmitic acid to inhibit cell proliferation and induce cleaved caspase 3 activity. Collectively, this study provides new insight into the effect of palmitic acid on cell proliferation and invasion and the formation of lipid droplets that may have potential clinical relevance in the treatment of obesity-driven endometrial cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Defects in BRCA1/2, which are tumor suppressor genes involved in the process of homologous recombination repair, can result in ovarian cancer. Poly (ADP-ribose) polymerase (PARP) inhibitors target these defects by further preventing DNA repair. Molecular analysis demonstrates a high rate of loss of heterozygosity (LOH) in patients with germline BRCA1/2 mutations and/or those with BRCA-associated cancers. Conversely, LOH is rare in patients with somatic BRCA1/2 mutations, prompting hypotheses that tumors with somatic BRCA mutations have a distinct phenotype compared with tumors with germline BRCA mutations. Treatment guidelines recommend using PARP inhibitors in patients with germline or somatic BRCA mutations for ovarian cancer maintenance therapy. However, the duration of maintenance therapy with PARP inhibitors based on germline versus somatic mutation status has not been directly compared, and many prospective trials included a small number of patients with somatic BRCA mutation tumors. OBJECTIVE: To compare the duration of maintenance therapy with PARP inhibitors in patients with ovarian cancer with germline BRCA mutations versus somatic BRCA mutations. METHODS: This single-center, retrospective, observational analysis included adults with ovarian cancer who were receiving maintenance therapy with PARP inhibitors at UNC Medical Center between December 2018 and April 2021. The primary outcome was the duration of maintenance therapy with PARP inhibitors. The secondary outcomes included the rate of dose interruptions, reductions, and discontinuation resulting from adverse events and the rate of LOH testing. RESULTS: A total of 21 patients met the study's eligibility criteria, of which 14 (67%) patients had a BRCA1 mutation (11 germline BRCA mutations and 3 somatic BRCA mutations). The remaining 7 (33%) patients had a BRCA2 mutation (6 germline BRCA mutations and 1 somatic BRCA mutation). The median duration of PARP inhibitor therapy was 18.5 months for patients with a germline BRCA mutation and 20.1 months for those with a somatic BRCA mutation (P=.46). Most of the study patients had dose interruptions (60% each in the germline BRCA and somatic BRCA mutation groups) and/or reductions (60% with germline BRCA mutation vs 80% with somatic BRCA mutation) as a result of adverse events during the study period. The discontinuation of treatment with PARP inhibitors as a result of adverse events was 30% in the germline BRCA mutation group versus 20% in the patients with a somatic BRCA mutation. None of the 21 patients in the study had LOH testing. CONCLUSION: Among the patients with ovarian cancer who received maintenance therapy with PARP inhibitors, there was no significant difference in the duration of the therapy with PARP inhibitors between the patients with germline BRCA mutation and those with somatic BRCA mutation. Larger patient populations and more data regarding the correlation of LOH to the response rate are needed to determine the best biomarker to predict a benefit from maintenance therapy with PARP inhibitors. [ABSTRACT FROM AUTHOR]

Ipatasertib (IPAT) is an orally administered, selective protein kinase B (AKT) inhibitor with promising data in solid tumors in both pre-clinical studies and clinical trials. Given that the PI3K/AKT/mTOR pathway is frequently dysregulated in uterine serous carcinoma (USC), we aimed to explore the functional impact of IPAT on anti-tumorigenic activity in USC cell lines and primary cultures of USC. We found that IPAT significantly inhibited cell proliferation and colony formation in a dose-dependent manner in USC cells. Induction of cell cycle arrest and apoptosis was observed in IPAT-treated ARK1 and SPEC-2 cells. Treatment with IPAT resulted in reduced adhesion and invasion of both cell lines with a concomitant decrease in the expression of Snail, Slug, and N-Cadherin. Compared with single-drug treatment, the combination of IPAT and paclitaxel synergistically reduced cell proliferation and increased the activity of cleaved caspase 3 in both cell lines. Additionally, IPAT inhibited growth in four of five primary USC cultures, and three of five primary cultures also exhibited synergistic growth inhibition when paclitaxel and IPAT were combined. These results support that IPAT appears to be a promising targeted agent in the treatment of USC., Competing Interests: None., (AJCR Copyright © 2022.)

Objective: To estimate the incidence and identify risk factors for atypical endometrial hyperplasia (AH) and endometrial cancer (EC) in American women undergoing infertility evaluation., Design: Case-control study., Setting: Academic reproductive endocrinology and infertility practice., Patients: Female patients (18-50 years) seeking infertility evaluation from January 1, 2009 to December 1, 2018. Patients with known genetic predisposition to cancer or prior cancer diagnosis were excluded. Cases were defined as patients diagnosed with AH or EC during infertility workup (n = 22). Controls without AH or EC were randomly selected in a 10:1 ratio (n = 220) from all women undergoing infertility evaluation in the same year., Interventions: None., Main Outcome Measures: Incidence of AH or EC and odds of AH or EC accounting for age, race, body mass index (BMI), and ovulatory dysfunction., Results: Twenty-two cases of AH or EC were identified among 11,569 women undergoing infertility evaluation (incidence 2 per 1,000 women, 95% confidence interval [CI] 1.2-2.9 per 1,000). Of these women, 68% had a BMI ≥30 kg/m 2 compared with 25% of controls. In multivariable analyses, women with a BMI ≥30 kg/m 2 were 5.9 times more likely to be diagnosed with AH or EC (adjusted odds ratio 5.9, 95% CI 2.0-17.2). Women with ovulatory dysfunction were 3.4 times more likely to be diagnosed with AH or EC (adjusted odds ratio 3.4, 95% CI 1.1-10.1)., Conclusions: The incidence of AH and EC in a population of women undergoing infertility evaluation is 10 times that in the general population of premenopausal women. Obesity is the strongest independent risk factor for AH and EC in women with infertility.