A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance.

To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic-features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.

Racial and Ethnic Disparities in Gynecologic Carcinosarcoma: A Single-Institution Experience.

We aimed to determine the incidence, treatment regimen, and treatment outcomes (including progression-free survival and overall survival) of gynecologic carcinosarcoma, a rare, aggressive, and understudied gynecologic malignancy. This retrospective review included all patients with gynecologic cancers diagnosed and treated at a single tertiary care comprehensive cancer center between January 2012 and May 2021. A total of 2116 patients were eligible for review, of which 84 cases were identified as carcinosarcoma: 66 were uterine (5.2% of uterine cancers), 17 were ovarian (3.6% of ovarian cancers), 1 was cervical (0.28% of cervical cancers), and 1 was untyped. Of the patients, 76.2% presented advanced-stage disease (stage III/IV) at the time of diagnosis. Minority patients were more likely to present with stage III/IV (p < 0.0001). The majority of patients underwent surgical resection followed by systemic chemotherapy with carboplatin and paclitaxel. The median PFS was 7.5 months. Of the patients, 55% were alive 1 year after diagnosis, and 45% were alive at 5 years. In the studied population, minorities were more likely to present with more advanced disease. The rate of gynecologic carcinosarcomas was consistent with historical reports.

Genetic Testing in the Latinx community: Impact of acculturation and provider relationships.

OBJECTIVES: The current study aimed to explore attitudes toward genetic germline testing and intentions to test in Latinas from Southern California. We hypothesized that patients' acculturation and education levels, as well as comfort with health care providers, are positively associated with attitudes and intentions toward genetic testing. METHODS: A survey was offered concurrently to Latinx female patients at a gynecologic oncology practice and to unaffiliated Latinx community members. The survey assessed demographics, structural, psychosocial, and acculturation factors and genetic testing attitudes and intentions via validated scales. RESULTS: Of 148 surveys collected, 66% of responders had low levels of acculturation. 50% of women had government-subsidized insurance; 22% had no schooling in the US. 67% of participants did not carry a diagnosis of cancer. Women with higher acculturation levels were more likely to consider genetic testing (rs = 0.54, p = .001). Higher acculturated women and less acculturated women under 50 were more likely to consider testing if it had been recommended by a female, trusted, or Hispanic/Latinx provider (rs = 0.22, p = .01, rs = 0.27, p = .003 and rs = 0.19, p = .003, respectively) or if there was a recent cancer diagnosis (self or family, rs = 0.19, p = .03). Overall, education correlated with intention to test. The more education outside of the US, the less negative was the attitude toward being tested (rs = -0.41, p = .002). CONCLUSIONS: Direct experiences with cancer, more schooling and higher acculturation coupled with provider characteristics determined if Latinas were more open to testing. Provider characteristics mattered: having a female, Latinx, Spanish speaking provider was important for genetic testing decision-making. These findings are particularly pertinent in areas with high Latinx populations.

Margin Status Post Cervical Conization Predicts Residual Adenocarcinoma In Situ (AIS) and Occult Adenocarcinoma in a Predominantly Hispanic Population.

Background: Adenocarcinoma in situ (AIS) of the cervix, is increasing in incidence, particularly in women of reproductive age. Fertility preservation is often desired. In a predominantly Hispanic population, we sought to determine the incidence of occult cervical cancer co-existing with AIS, and evaluate how conization margin status correlates with residual disease upon hysterectomy. Methods: A retrospective study utilizing a comprehensive cancer center database was conducted. Data from patients with histologically proven AIS of the cervix were abstracted. Results: Of 47 patients that met the criteria, 23 (49%) were Hispanic, 21 (45%) were White, two (4%) were Asian, and one (2%) was Black. The median age was 37. Forty-two patients underwent cervical conizations; 13/42 (48%) had positive margins upon conization; 28/42 (67%) underwent hysterectomies. Furthermore, 6/13 (46%) patients with positive conization margins had residual disease in hysterectomy specimens, with 2/13 (15%) found to have invasive cancer. In contrast, 0/14 (0%) of patients with negative margins had residual disease (p = 0.036, Chi-squared 4.41, df = 1). In total, 2/27 (7%) patients who underwent hysterectomies had invasive cancer (7%). Conclusions: Positive margins upon cervical conization for AIS of the cervix were correlated with a relatively high rate of residual AIS and occult invasive cancer. Negative conization margins were correlated with no residual disease. Those patients may be candidates for fertility-sparing treatment.

Let-7i Reduces Aggressive Phenotype and Induces BRCAness in Ovarian Cancer Cells.

High-grade serous carcinoma of the ovary is a deadly gynecological cancer with poor long-term survival. Dysregulation of microRNAs has been shown to contribute to the formation of cancer stem cells (CSCs), an important part of oncogenesis and tumor progression. The let-7 family of microRNAs has previously been shown to regulate stemness and has tumor suppressive actions in a variety of cancers, including ovarian. Here, we demonstrate tumor suppressor actions of let-7i: repression of cancer cell stemness, inhibition of migration and invasion, and promotion of apoptosis, features important for cancer progression, relapse, and metastasis. Let-7i over-expression results in increased sensitivity to the PARP inhibitor olaparib in samples without BRCA mutations, consistent with induction of BRCAness phenotype. We also show that let-7i inhibits the expression of several factors involved in the homologous recombination repair (HRR) pathway, providing potential mechanisms by which the BRCAness phenotype could be induced. These actions of let-7i add to the rationale for use of this miRNA as a treatment for ovarian cancer patients, including those without mutations in the HRR pathway.

When the balloon goes up, blood transfusion goes down: a pilot study of REBOA in placenta accreta spectrum disorders.

BACKGROUND: Patients with placenta accreta spectrum (PAS) disorders often suffer massive hemorrhage during cesarean hysterectomies (CHyst). A novel strategy to decrease blood loss and minimize perioperative morbidity associated with PAS is utilization of ER-REBOA Catheter intraoperatively. In this study, we explore the use of ER-REBOA Catheter during CHyst with the goal of minimizing perioperative morbidity and packed red blood cell (PRBC) transfusions. METHODS: We conducted a retrospective case-control study at a regional referral center of consecutive patients with PAS undergoing CHyst. The primary outcomes were PRBC transfusions of ≥4 units. Secondary outcomes included surgical intensive care unit admissions, postoperative length of stay (LOS), postoperative ileus, and vascular complication rate. We also explored utilization of manual palpation and omission of precesarean fluoroscopy for resuscitative endovascular balloon occlusion of the aorta (REBOA) placement verification in distal aortic zone 3. RESULTS: 90 patients were included in the study. REBOA and non-REBOA cases were similar in clinicodemographic characteristics. 17.7% of REBOA cases received ≥4 units of PRBC compared with 49.3% of non-REBOA cases (p=0.03). Zero REBOA patients developed postoperative ileus, whereas 18 (25%) non-REBOA patients did (p=0.02). LOS was reduced in the REBOA group. Postplacement fluoroscopy was omitted in all REBOA cases. Two postoperative arterial thrombotic events (2 of 19, 11% of REBOA patients) were identified in the REBOA group, one requiring a thrombectomy (1 of 19, 5%). DISCUSSION: Decrease in blood transfusions of ≥4 units of PRBC is demonstrated when ER-REBOA Catheter is placed in distal aortic zone 3 during CHyst performed for severe PAS disorders. The incidence of postoperative ileus and LOS are reduced in the ER-REBOA Catheter group. Placement and utilization of ER-REBOA Catheter during CHyst may be feasible without fluoroscopy when manual placement verification is performed by an experienced operator. Protocol modifications focusing on reducing thrombotic rate are ongoing. LEVEL OF EVIDENCE: IV.

The Epithelial-Mesenchymal Transcription Factor SNAI1 Represses Transcription of the Tumor Suppressor miRNA let-7 in Cancer.

We aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer, and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.

Epithelial/mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with miRNA let-7 levels and predicts tumor growth and metastasis.

Patient-derived samples present an advantage over current cell line models of high-grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient-derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient-derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial-to-mesenchymal state. Samples with a stronger epithelial phenotype were more active in self-renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let-7 (lethal-7) expression and stemness, consistent with the loss of let-7 being an important component of the cancer stem cell phenotype. We observed that lower let-7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let-7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let-7 levels. We conclude that let-7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo.

Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer.

Abnormal regulation and expression of microRNAs (miRNAs) has been documented in various diseases including cancer. The miRNA let-7 (MIRLET7) family controls developmental timing and differentiation. Let-7 loss contributes to carcinogenesis via an increase in its target oncogenes and stemness factors. Let-7 targets include genes regulating the cell cycle, cell signaling, and maintenance of differentiation. It is categorized as a tumor suppressor because it reduces cancer aggressiveness, chemoresistance, and radioresistance. However, in rare situations let-7 acts as an oncogene, increasing cancer migration, invasion, chemoresistance, and expression of genes associated with progression and metastasis. Here, we review let-7 function as tumor suppressor and oncogene, considering let-7 as a potential diagnostic and prognostic marker, and a therapeutic target for cancer treatment. We explain the complex regulation and function of different let-7 family members, pointing to abnormal processes involved in carcinogenesis. Let-7 is a promising option to complement conventional cancer therapy, but requires a tumor specific delivery method to avoid toxicity. While let-7 therapy is not yet established, we make the case that assessing its tumor presence is crucial when choosing therapy. Clinical data demonstrate that let-7 can be used as a biomarker for rational precision medicine decisions, resulting in improved patient survival.

Brachytherapy: A critical component of primary radiation therapy for cervical cancer: From the Society of Gynecologic Oncology (SGO) and the American Brachytherapy Society (ABS).

Brachytherapy is well-established as an integral component in the standard of care for treatment of patients receiving primary radiotherapy for cervical cancer. A decline in brachytherapy has been associated with negative impacts on survival in the era of modern EBRT techniques. Conformal external beam therapies such intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT) should not be used as alternatives to brachytherapy in patients undergoing primary curative-intent radiation therapy for cervical cancer. Computed tomography or magnetic resonance image-guided adaptive brachytherapy is evolving as the preferred brachytherapy method. With careful care coordination EBRT and brachytherapy can be successfully delivered at different treatment centers without compromising treatment time and outcome in areas where access to brachytherapy maybe limited.

Brachytherapy: A critical component of primary radiation therapy for cervical cancer: From the Society of Gynecologic Oncology (SGO) and the American Brachytherapy Society (ABS).

Brachytherapy is well-established as an integral component in the standard of care for treatment of patients receiving primary radiotherapy for cervical cancer. A decline in brachytherapy has been associated with negative impacts on survival in the era of modern EBRT techniques. Conformal external beam therapies such intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT) should not be used as alternatives to brachytherapy in patients undergoing primary curative-intent radiation therapy for cervical cancer. Computed tomography or magnetic resonance image-guided adaptive brachytherapy is evolving as the preferred brachytherapy method. With careful care coordination EBRT and brachytherapy can be successfully delivered at different treatment centers without compromising treatment time and outcome in areas where access to brachytherapy maybe limited.

Survival of Cervical Cancer Patients Presenting with Occult Supraclavicular Metastases Detected by FDG-Positron Emission Tomography/CT: Impact of Disease Extent and Treatment.

AIMS: The study aimed to do the following: (1) describe progression free survival (PFS) and overall survival (OS) of women with cervical cancer presenting with occult supraclavicular lymph node (SCLN) metastases, identified by positron emission tomography CT (PET-CT) and (2) compare OS of patients with isolated SCLN metastases to that of patients with SCLN and extranodal metastatic disease. METHODS: Patients were identified retrospectively. Treatment intent was abstracted. PFS and OS in the high-dose chemo-radiotherapy (RT), palliative RT, and supportive treatment groups, as well as OS of patients with SCLN metastases only vs. SCLN and extranodal metastases were calculated. RESULTS: Fourteen patients received high-dose chemo-RT, 32 received palliative RT, and 6 received supportive care (n = 52). Median PFS was 3 months in high-dose chemo-RT group and 1 month in palliative RT (p = ns). Median OS was 12 months in high-dose chemo-RT group, 7 months in palliative RT group, and 2 months in palliative care group (p = 0.05). OS was significantly different between patients with isolated SCLN disease vs. SCLN and extranodal disease, that is, 10.5 vs. 3 months (p = 0.009, χ2 = 6.9). CONCLUSIONS: In this limited analysis, median OS of cervical cancer patients with PET/CT-positive SCLN metastases was the longest when treated with high-dose chemo-RT. Patients with SCLN and extranodal metastases experienced significantly shorter OS, as compared to patients with SCLN only disease.

Combined ultrasound-curcumin treatment of human cervical cancer cells.

OBJECTIVES: Human papillomavirus (HPV) is associated with cervical cancer. Studies showed curcumin inhibits HPV oncogenes expression but curcumin has low bioavailability. The objectives were: (1) to study ultrasound enhancement of curcumin effects on HeLa, SiHa and C33A, (2) to compare two frequencies for sonoporation and (3) to detect cell-free DNA released by the treatment. STUDY DESIGN: HeLa, SiHa and C33A cells (non-HPV control) were processed and exposed to either: (1) 10µM curcumin only, (2) 10µM curcumin with 8s of 7.5MHz ultrasound, (3) 10µM curcumin with 8s of 5.0MHz ultrasound, (4) control medium, or (5) 8s of 7.5MHz ultrasound. The five treated groups were incubated (48h) and analyzed by dual fluorescence apoptosis/necrosis assay. DNA in spent media was analyzed by capillary analysis. RESULTS: Combined curcumin ultrasound resulted in 9-, 12- and 16-fold higher necrosis in HeLa, SiHa and C33A cells respectively. Increased necrosis correlated with higher ultrasound frequencies. There was increased apoptosis in HeLa or SiHa cells with the combined treatment. Curcumin alone resulted in a lesser 2-4-fold increase in necrosis in the groups. Cell-free DNA was detected in the spent media of HeLa and SiHa but not C33A cultures. CONCLUSIONS: The results showed enhanced necrosis in cervical carcinoma cell lines after combined treatment and confirmed the ultrasound capacity to increase effectiveness of curcumin. Cancer cells were smaller post-treatment suggesting microtubule structural disruption. Cell-free DNA was low molecular weight consistent with lysed host cell.

A phase II trial of a surgical protocol to decrease the incidence of wound complications in obese gynecologic oncology patients.

OBJECTIVES: Obese women have a high incidence of wound separation after gynecologic surgery. We explored the effect of a prospective care pathway on the incidence of wound complications. METHODS: Women with a body mass index (BMI) ≥30 kg/m(2) undergoing a gynecologic procedure by a gynecologic oncologist via a vertical abdominal incision were eligible. The surgical protocol required: skin and subcutaneous tissues to be incised using a scalpel or cutting electrocautery, fascial closure using #1 polydioxanone suture, placement of a 7 mm Jackson-Pratt drain below Camper's fascia, closure of Camper's fascia with 3-0 plain catgut suture and skin closure with staples. Wound complication was defined as the presence of either a wound infection or any separation. Demographic and perioperative data were analyzed using contingency tables. Univariable and multivariable regression models were used to identify predictors of wound complications. Patients were compared using a multivariable model to a historical group of obese patients to assess the efficacy of the care pathway. RESULTS: 105 women were enrolled with a median BMI of 38.1. Overall, 39 (37%) had a wound complication. Women with a BMI of 30-39.9 kg/m(2) had a significantly lower risk of wound complication as compared to those with a BMI >40 kg/m(2) (23% vs 59%, p<0.001). After controlling for factors associated with wound complications the prospective care pathway was associated with a significantly decreased wound complication rate in women with BMI <40 kg/m(2) (OR 0.40, 95% C.I.: 0.18-0.89). CONCLUSION: This surgical protocol leads to a decreased rate of wound complications among women with a BMI of 30-39.9 kg/m(2).

Low yield of residual vulvar carcinoma and dysplasia upon re-excision for close or positive margins.

OBJECTIVES: The objectives of this study are to determine the utility of re-excision after a primary diagnosis of vulvar carcinoma by assessing the frequency of residual carcinoma found upon re-excision and to quantitate the wound breakdown and carcinoma recurrence rates. METHODS: We reviewed 1122 cases of VIN or vulvar carcinoma. Women who underwent re-excisional procedures, as part of their initial surgical treatment were identified. Associations between the margin status of the original excisional sample and histology of re-excision, as well as association between the depth of invasion upon initial excision and histology of re-excision were analyzed with Chi-square tests. RESULTS: We identified 84 evaluable patients, 72 with stage I disease, 4 with stage II, and 7 with stage III disease. Upon the initial excisional procedure, 33 patients (39%) had carcinoma-positive margins, 27 patients had VIN-positive margins (32%) and 24 patients (28%) had negative margins (>1mm). Upon re-excision, 1/24 (4%) patients with negative margins, 2/27 (7%) patients with VIN-positive margins, and 11/33 (33%) patients with carcinoma-positive margins were found to have carcinoma in the re-excision specimens (p<0.0001, χ(2)=31). Deeper tumor invasion of the initial excisional specimen (1-12mm) was associated with a higher chance of finding carcinoma upon re-excision (range 18-42%, depending on depth of invasion) (p=0.015, χ(2)=19). Nineteen patients (23%) had vulvar wound breakdown post re-excision. Twelve patients (15%) experienced recurrences. CONCLUSIONS: The yield of micro- or invasive carcinoma at re-excision is low, with a high wound breakdown rate. Re-excision should be considered for patients with margins positive for carcinoma, especially for women with deep invasion, while women with VIN or close but clear margins may be followed.

Phosphatase and tensin homolog (PTEN) pseudogene expression in endometrial cancer: a conserved regulatory mechanism important in tumorigenesis?

OBJECTIVES: The PTEN pseudogene, PTENP1, was recently shown to play a role in cell proliferation in a prostate cancer model. In the present study, we sought to determine whether PTENP1 is expressed in endometrial cancer (EMCA) cell lines and primary tumors along with the microRNAs (miRNAs) that are predicted to regulate PTEN and PTENP1 transcript levels. METHODS: RNA was prepared from six EMCA cell lines, three normal endometrial samples, and 61 primary tumors. TaqMan® RT-PCR was used to quantitate PTEN expression in all specimens and PTENP1 expression in cell lines, and normal endometrial (NE) samples. PTENP1 expression was evaluated using conventional RT-PCR in primary tumors. MicroRNA profiling was undertaken using NanoString(TM) technology in AN3CA and KLE cell lines. The relationship between PTEN transcript levels, PTENP1 expression, and PTEN mutation status was investigated. RESULTS: All NE samples, cell lines, and primary tumors expressed PTEN. PTENP1 transcript was expressed in NE, cell lines, and 34/61 (56%) primary tumors. The median relative PTEN level was 2.9 arbitrary expression units in PTENP1-positive tumors and 2.3 in PTENP1-negative tumors (p=0.09). PTEN levels in wild-type and haploinsufficient tumors were variable compared to PTEN-null tumors (p=0.015). Four microRNAs predicted to bind PTEN/PTENP1 ranked in the top 20 most abundant microRNA subtypes in the AN3CA and KLE cell lines. CONCLUSIONS: PTENP1 is expressed in NE and EMCA cell lines, as are PTEN/PTENP1 targeting inhibitory miRNAs (cell lines). Further studies are needed to evaluate the impact of PTEN/PTENP1/miRNA interactions on tumorigenesis regulation in EMCA.

Effect of cigarette smoking on epithelial ovarian cancer survival.

OBJECTIVE: To determine associations between smoking and survival in patients with ovarian cancer. STUDY DESIGN: We performed a retrospective review of patients undergoing surgery for ovarian cancer. Abstracted patient data included age, smoking history, stage, grade, extent of cytoreduction, and survival. Data were examined with Fisher's exact test, Kaplan-Meier survival analysis, and Cox regression analysis. RESULTS: A total of 130 patients met criteria for review. Seventeen (13%) smoked cigarettes at the time of initial laparotomy. Twenty-one (16%) were left with > 1 cm residual disease. Smoking did not correlate with the incidence of suboptimal cytoreduction. There were no statistical differences in incidence of hypertension, obesity, or coronary artery disease in smokers compared to nonsmokers. Smoking was found to negatively influence length of progression-free survival. Similarly, smokers were found to have decreased disease-specific overall survival compared to nonsmokers. Cigarette smoking retained independent significance as poor prognostic factors, after controlling for age, stage, and grade. CONCLUSION: These findings identify a negative correlation with cigarette smoking and survival in women with ovarian cancer. Further studies are proposed to elucidate the molecular mechanisms underlying these clinical observations.

A role for BRCA1 in uterine leiomyosarcoma.

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)-driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS.