FANCF methylation contributes to chemoselectivity in ovarian cancer

AbstractA new model of ovarian cancer tumor progression implicates aberrant FANCF promoter methylation that is associated with gene silencing and disruption of the Fanconi-anemia-BRCA pathway. Disruption of the pathway occurs de novo in ovarian cancers and may contribute to selective sensitivity to platinum salts

Socioeconomic and Geographic Differences in Mammography Trends Following the 2009 USPSTF Policy Update

Importance: In 2024, the US Preventive Services Task Force (USPSTF) reversed a 2009 policy recommending only females aged 50 to 74 years complete a biennial mammogram. Understanding whether females facing heterogeneous breast cancer risks responded to the 2009 guidance may illuminate how they may respond to the latest policy update. Objective: To evaluate whether the 2009 policy was associated with changes in mammography screening in females no longer recommended to complete a biennial mammogram and whether these changes varied by factors associated with breast cancer risk. Design, Setting, and Participants: The difference-in-differences design compared biennial mammogram trends in the exposed groups (aged 40-49 and ≥75 years) with trends of the unexposed groups (aged 50-64 and 65-74 years), before and after the 2009 update. Population-based, repeated cross-sectional survey data came from the Behavioral Risk Factor Surveillance System (BRFSS) biennial cancer screening module (2000-2018). The sample was restricted to females between ages 40 and 84 years. Data were analyzed from March 1 to June 30, 2024. Main Outcomes and Measures: The outcome was a binary variable indicating whether the respondent reported a mammogram in the past 2 years (biennial). After 2009, females aged 40 to 49 and 75 or older years were exposed to the policy update, as a complete biennial mammogram was recommended. Subgroup analyses included race and ethnicity, educational level, household income, smoking history, current binge drinking status, and state of residence. Results: The sample included 1 594 834 females; 75% reported a biennial mammogram. In those aged 40 to 49 years, the USPSTF update was associated with a 1.1 percentage-point (95% CI, −1.8% to −0.3 percentage points) decrease in the probability of a biennial mammogram, with the largest decreases in the non-Hispanic Black population (−3.0 percentage points; 95% CI, −5.5% to −0.5 percentage points). In the aged 75 years or older group, the USPSTF update was associated with a 4.8 percentage-point decrease (95% CI, −6.3% to −3.5 percentage points) in the probability of a biennial mammogram, with significant heterogeneity by race and ethnicity, binge drinking status, and state residence. Conclusions and Relevance: In this study, socioeconomic factors were associated with differences in how females responded to the 2009 USPSTF mammography recommendation. Whether the 2024 update considered such differences is unclear. These findings suggest that including risk assessment into future USPSTF policy updates may improve adoption of risk-reducing interventions and shorten the time to diagnosis and treatment for high-risk patients.</p

β-Catenin is required for the tumorigenic behavior of triple-negative breast cancer cells

Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether β-catenin was necessary for tumorigenic behaviors in vivo and in vitro. β-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of β-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that β-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, β-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. β-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and form anchorage-independent colonies in soft agar. β-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that β-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity

Afatinib efficacy against squamous cell carcinoma of the head and neck cell lines in vitro and in vivo.

Epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in squamous cell carcinoma of the head and neck (SCCHN). In addition to EGFR, other ErbB family members are expressed and activated in SCCHN. Afatinib is an ErbB family blocker that has been approved for treating patients with EGFR-mutated nonsmall cell lung cancer. We sought to determine the efficacy of afatinib in preclinical models and compare this to other EGFR-targeted agents. Afatinib efficacy was characterized in a panel of ten SCCHN cell lines and found to be most effective against cell lines amplified for EGFR. Afatinib had lower IC(50) values than did gefitinib against the same panel. Two EGFR-amplified cell lines that are resistant to gefitinib are sensitive to afatinib. Cetuximab was not found to have a synergistic effect with afatinib either in vitro or in vivo. Both afatinib and cetuximab were effective in tumor xenograft model. Afatinib is an effective agent in SCCHN especially in models with EGFR amplification

Regulation of Tcf7l1 DNA Binding and Protein Stability as Principal Mechanisms of Wnt/β-Catenin Signaling

SummaryWnt/β-catenin signal transduction requires direct binding of β-catenin to Tcf/Lef proteins, an event that is classically associated with stimulating transcription by recruiting coactivators. This molecular cascade plays critical roles throughout embryonic development and normal postnatal life by affecting stem cell characteristics and tumor formation. Here, we show that this pathway utilizes a fundamentally different mechanism to regulate Tcf7l1 (formerly named Tcf3) activity. β-catenin inactivates Tcf7l1 without a switch to a coactivator complex by removing it from DNA, which leads to Tcf7l1 protein degradation. Mouse genetic experiments demonstrate that Tcf7l1 inactivation is the only required effect of the Tcf7l1-β-catenin interaction. Given the expression of Tcf7l1 in pluripotent embryonic and adult stem cells, as well as in poorly differentiated breast cancer, these findings provide mechanistic insights into the regulation of pluripotency and the role of Wnt/β-catenin in breast cancer

c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells

Abstract Background The BRCA1 gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate BRCA1 expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that BRCA1 is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of BRCA1 by c-Myc. Methods c-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells. BRCA1 mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and BRCA1 promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the BRCA1 promoter region. The association of c-Myc with the BRCA1 promoter in vivo was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the BRCA1 promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay. Results Depletion of c-Myc was found to be correlated with reduced expression levels of BRCA1 mRNA and BRCA1 protein. Depletion of c-Myc decreased BRCA1 promoter activity, while ectopically expressed c-Myc increased BRCA1 promoter activity. In the distal BRCA1 promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions in vivo. Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc-dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity. Conclusions The distal BRCA1 promoter region is associated with c-Myc and contributes to BRCA1 gene activation. </jats:sec

Willingness to Implement Narrative Communication Interventions: Mixed Methods Study Among Breast Cancer Patients and Survivors at the University College Hospital, Ibadan, Nigeria

Purpose: Globally, black women experience poorer breast cancer outcomes suggesting the need for effective health promotion approaches to increase perceived susceptibility and improve screening practices. Although narrative communication by patients or survivors is increasingly considered an effective approach for better breast cancer outcomes, there is limited information on its use in Nigeria. This study assessed the perception, willingness and generalized self-efficacy of breast cancer patients and survivors at the University College Hospital, Ibadan, to implement narrative communication interventions. Material and Methods: This was a cross-sectional study, and a mixed-method convergent parallel design was utilized for data collection. Written informed consent was obtained from each study participant for in-depth interviews and a semi-structured questionnaire. Five patients were recruited for in-depth interviews and a semi-structured questionnaire was used to obtain data from 102 patients. Data were analysed using thematic analysis for qualitative data, and descriptive and inferential statistics for quantitative data. Results: The mean age of the respondents was 49.3 ± 10.2 years. There was a good perception (97.1%) towards narrative communication interventions. Ninety-eight percent were willing to implement narrative communication interventions and 79.4% had a high generalized self-efficacy. Respondents’ educational attainment was significantly associated with the generalized self-efficacy to implement narrative communication intervention programs (P Conclusion: This study highlights the potential of breast cancer patients and survivors as breast health educators, sharing their lived experiences to empower and motivate women on prevention and screening. Findings could guide the design of population-level, breast cancer prevention and screening interventions.</p

Single-cell chemoproteomics identifies metastatic activity signatures in breast cancer

Protein activity state, rather than protein or mRNA abundance, is a biologically regulated and relevant input to many processes in signaling, differentiation, development, and diseases such as cancer. While there are numerous methods to detect and quantify mRNA and protein abundance in biological samples, there are no general approaches to detect and quantify endogenous protein activity with single-cell resolution. Here, we report the development of a chemoproteomic platform, single-cell activity-dependent proximity ligation, which uses automated, microfluidics-based single-cell capture and nanoliter volume manipulations to convert the interactions of family-wide chemical activity probes with native protein targets into multiplexed, amplifiable oligonucleotide barcodes. We demonstrate accurate, reproducible, and multiplexed quantitation of a six-enzyme (Ag-6) panel with known ties to cancer cell aggressiveness directly in single cells. We further identified increased Ag-6 enzyme activity across breast cancer cell lines of increasing metastatic potential, as well as in primary patient-derived tumor cells and organoids from patients with breast cancer

Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma

Microarray profiling of invasive breast carcinomas has identified five distinct subtypes of tumors (luminal A, luminal B, normal breast-like, HER2 overexpressing, and basal-like) that are associated with different clinical outcomes. The basal-like subtype is associated with poor clinical outcomes and is the subtype observed in BRCA1-related breast cancers. The aim of this study was to characterize the histologic and immunophenotypic properties of breast basal-like carcinomas that were first positively identified using DNA microarray analysis. Detailed histologic review was performed on 56 tumors with known microarray profiles (23 basal-like, 23 luminal, and 12 HER2+). Immunohistochemistry for estrogen receptor (ER), HER2, EGFR, smooth muscle actin (SMA), p63, CD10, cytokeratin 5/6, cytokeratin 8/18, and vimentin was performed on 18 basal-like, 16 luminal, and 12 HER2+ tumors. The basal-like tumors were grade 3 ductal/NOS (21/23) or metaplastic (2/23) carcinomas that frequently showed geographic necrosis (17/23), a pushing border of invasion (14/23), and a stromal lymphocytic response (13/23). Most basal-like tumors showed immunoreactivity for vimentin (17/18), luminal cytokeratin 8/18 (15/18), EGFR (13/18), and cytokeratin 5/6 (11/18), while positivity for the myoepithelial markers SMA (4/18), p63 (4/18) and CD10 (2/18) was infrequent. All basal-like tumors tested were ER− and HER2−. Morphologic features significantly associated with the basal-like subtype included markedly elevated mitotic count (P less than 0.0001), geographic tumor necrosis (P=0.0003), pushing margin of invasion (P=0.0001), and stromal lymphocytic response (P=0.01). The most consistent immunophenotype seen in the basal-like tumors was negativity for ER and HER2, and positivity for vimentin, EGFR, cytokeratin 8/18, and cytokeratin 5/6. The infrequent expression of myoepithelial markers in basal-like carcinomas does not support a direct myoepithelial cell derivation of these tumors. These findings should further assist in the identification of basal-like carcinomas in clinical specimens, facilitating treatment and epidemiologic studies of this tumor subtype