Background: To investigate the global expression profile of miRNAs, their impact on cellular sign... more Background: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC).Methods: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions.Results: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seve...
Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR),... more Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR), estrogen (ER), progesterone (PR) receptors and human epidermal growth factor (HER2) expression. This subset of triple negative breast cancer (TNBC) has been described as unique to African American (AA) women and represents about 67-90% of all TNBC. Yet, there are limited clinical and therapeutic studies focused on this new subset of breast cancer (BCa) that is highly aggressive and portends a worse survival compared to AR positive Bca subtypes. The objectives of our study were to 1) determine the molecular and clinical characteristics of QNBC and compare them with other BCa subtypes and 2) determine the association of QNBC with clinicopathological factors and prognostic markers. Materials and Methods: Tissue arrays were constructed from FFPE tumor blocks of invasive ductal breast carcinomas in 202 AAs, diagnosed at Howard University from 2000 to 2010. Two separate tissue cores of IDC represented each surgical case in the TMA and was linked to an Institutional Review Board-approved database of demographic and clinical data. Using a microtome, 5-µm sections were cut from the TMA blocks and mounted onto Superfrost Plus microscope slides. Sections were stained with a mouse monoclonal antibody against AR (Clone AR 441, DAKO). Immunohistochemistry for AR was considered positive if ≥10% of tumor cells showed nuclear staining. Bivariate analysis was performed via χ2 analysis and survival data was calculated via Kaplan-Meier curves (SPSS v28.0.0). Results: The most prevalent breast cancer subtype was luminal A (ER+ or PR+, HER2−; 43.5%), followed by TNBC (33.7%). Of the 67 TNBCs on the array, 63 had AR data; 33 (52%) of the TNBCs were AR negative. Greater than 70% of all tumors were stage I and II; and Grade 3 comprised 67.4% of the tumors. QNBC tumors were more likely to be higher grade (p<0.001) and larger in size (p=0.05) compared to other subtypes. There was also a trend for increased metastases in QNBCs (Luminal and HER2 tumors=11.2%; TNBC=13.3%; AR negative= 18.8%; and QNBC=20.8% (p=0.15)). Compared to TNBCs, QNBCs were larger (p=0.048), more likely to express markers associated invasion (Fascin, p=0.004) and reduced survival (Vimentin, p=0.014). There was a trend for increased expression of markers associated with metastases: Mammaglobin (expressed in 30.8% of TNBCs compared to 52.1% of QNBCs; p=0.17) and CD105 (expressed in 6.7% of TNBCs compared to 27.1% of QNBCs; p=0.097). There was no association between QNBC and stage, recurrence-free survival, or overall survival. Conclusion: In our study of AAs, a statistically significant association was noted between QNBC tumors and poorer prognosis. The high prevalence of AR negativity of TNBCs in AAs could explain observed worse outcomes and supports the existence of a unique subtype of Bca known as QNBC, worthy of scientific attention. Citation Format: Oluwadamilola Oladeru, Yasmine Kanaan, Tammy Naab, Luisel J. Ricks-Santi. Quadruple negative breast tumors in African American women express factors associated with worse prognosis compared to triple negative tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3682.
Among patients with triple-negative breast cancer (TNBC), several studies have suggested that der... more Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, ...
GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due t... more GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due to their robust and diffuse expression in mammary tissue. However, the expression of these markers has not been well characterized in tumors from African American women. The goal of this study was to characterize and evaluate the expression of GATA3 and mammaglobin breast tumors from African American women and determine their association with clinicopathological outcomes including breast cancer subtypes. Tissue microarrays (TMAs) were constructed from well preserved, morphologically representative tumors in archived formalin-fixed, paraffin-embedded (FFPE) surgical blocks from 202 patients with primary invasive ductal carcinoma. Mammaglobin, and GATA3 expression was assessed using immunohistochemistry (IHC). Univariate analysis was carried out to determine the association between expression of GATA3, mammaglobin and clinicopathological characteristics. Kaplan-Meier estimates of overall su...
Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR),... more Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR), estrogen (ER), progesterone (PR) receptors and human epidermal growth factor (HER2) expression. This subset of triple negative breast cancer (TNBC) has been described as unique to African American (AA) women and represents about 67-90% of all TNBC. Yet, there are limited clinical and therapeutic studies focused on this new subset of breast cancer (BCa) that is highly aggressive and portends a worse survival compared to AR positive Bca subtypes. The objectives of our study were to 1) determine the molecular and clinical characteristics of QNBC and compare them with other BCa subtypes and 2) determine the association of QNBC with clinicopathological factors and prognostic markers. Materials and Methods: Tissue arrays were constructed from FFPE tumor blocks of invasive ductal breast carcinomas in 202 AAs, diagnosed at Howard University from 2000 to 2010. Two separate tissue cores of IDC re...
Additional file 4: Table S3. Experimentally validated target genes of 33 selected miRNAs differen... more Additional file 4: Table S3. Experimentally validated target genes of 33 selected miRNAs differentially expressed in the three group comparisons. The Integrated Breast Cancer Pathway with miRNAs and experimentally validated target genes. Tumor size related miRs and target genes (pink), LN related miRs and target genes (orange), REC related miRs and target genes (blue), target genes associated with more than one comparison (green). Red lines represent inhibitory interaction, green lines represent stimulatory interaction, and black lines represent miRNA interaction with target.
1322 BRCA1/2 mutations were investigated in 99 independent families at elevated risk of germline ... more 1322 BRCA1/2 mutations were investigated in 99 independent families at elevated risk of germline mutations. Of the 99 high-risk families, 71 were families with multiple cases of breast cancer, 14 with multiple cases of breast and ovarian cancers, 8 with only early onset breast cancer (40 years or less), 3 with only bilateral breast cancer, 2 with male breast cancer, and 1 individual with breast and ovarian cancer. In this study, families were screened by denaturing high performance liquid chromatography (DHPLC). One deleterious BRCA1 mutation (5296delGAAA) was detected in two unrelated families. One of these families had 12 cases of breast cancer and 3 ovarian cancers, and the proband (tested individual) was diagnosed at age 32. The other family had 3 cases of breast cancer, 1 case of ovarian cancer, 2 cases of prostate cancer; and the proband was diagnosed at age 30 with estrogen/progesterone receptor-negative (ER-PR-) cancer. Early age of onset and ER-PR- tumors are characteristic...
Additional file 1: Table S1. Summary of the clinical and histopathological characteristics of the... more Additional file 1: Table S1. Summary of the clinical and histopathological characteristics of the TNBC-AA patients analyzed in this study.
Additional file 3: Table S2. MiRNAs that are significantly enriched and targets in Integrated Bre... more Additional file 3: Table S2. MiRNAs that are significantly enriched and targets in Integrated Breast Cancer Pathway in each clinical group evaluated. (P
Additional file 2: Figure S1. Principal Component Analysis (PCA) showing the clustering of the AA... more Additional file 2: Figure S1. Principal Component Analysis (PCA) showing the clustering of the AA patients (black dots) with the Africans, African Americans and African Caribbean groups based on genotype analysis. The horizontal axis represents Principal Component 1 (PC1) and vertical axis Principal Component 2 (PC2).
Additional file 5: Figure S2. The Integrated Breast Cancer Pathway with miRNAs and experimentally... more Additional file 5: Figure S2. The Integrated Breast Cancer Pathway with miRNAs and experimentally validated target genes. Tumor size related miRs and target genes (pink), LN related miRs and target genes (orange), REC related miRs and target genes (blue), target genes associated with more than one comparison (green). Red lines represent inhibitory interaction, green lines represent stimulatory interaction, and black lines represent miRNA interaction with target.
Background: To investigate the global expression profile of miRNAs, their impact on cellular sign... more Background: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC).Methods: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions.Results: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seve...
Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR),... more Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR), estrogen (ER), progesterone (PR) receptors and human epidermal growth factor (HER2) expression. This subset of triple negative breast cancer (TNBC) has been described as unique to African American (AA) women and represents about 67-90% of all TNBC. Yet, there are limited clinical and therapeutic studies focused on this new subset of breast cancer (BCa) that is highly aggressive and portends a worse survival compared to AR positive Bca subtypes. The objectives of our study were to 1) determine the molecular and clinical characteristics of QNBC and compare them with other BCa subtypes and 2) determine the association of QNBC with clinicopathological factors and prognostic markers. Materials and Methods: Tissue arrays were constructed from FFPE tumor blocks of invasive ductal breast carcinomas in 202 AAs, diagnosed at Howard University from 2000 to 2010. Two separate tissue cores of IDC represented each surgical case in the TMA and was linked to an Institutional Review Board-approved database of demographic and clinical data. Using a microtome, 5-µm sections were cut from the TMA blocks and mounted onto Superfrost Plus microscope slides. Sections were stained with a mouse monoclonal antibody against AR (Clone AR 441, DAKO). Immunohistochemistry for AR was considered positive if ≥10% of tumor cells showed nuclear staining. Bivariate analysis was performed via χ2 analysis and survival data was calculated via Kaplan-Meier curves (SPSS v28.0.0). Results: The most prevalent breast cancer subtype was luminal A (ER+ or PR+, HER2−; 43.5%), followed by TNBC (33.7%). Of the 67 TNBCs on the array, 63 had AR data; 33 (52%) of the TNBCs were AR negative. Greater than 70% of all tumors were stage I and II; and Grade 3 comprised 67.4% of the tumors. QNBC tumors were more likely to be higher grade (p<0.001) and larger in size (p=0.05) compared to other subtypes. There was also a trend for increased metastases in QNBCs (Luminal and HER2 tumors=11.2%; TNBC=13.3%; AR negative= 18.8%; and QNBC=20.8% (p=0.15)). Compared to TNBCs, QNBCs were larger (p=0.048), more likely to express markers associated invasion (Fascin, p=0.004) and reduced survival (Vimentin, p=0.014). There was a trend for increased expression of markers associated with metastases: Mammaglobin (expressed in 30.8% of TNBCs compared to 52.1% of QNBCs; p=0.17) and CD105 (expressed in 6.7% of TNBCs compared to 27.1% of QNBCs; p=0.097). There was no association between QNBC and stage, recurrence-free survival, or overall survival. Conclusion: In our study of AAs, a statistically significant association was noted between QNBC tumors and poorer prognosis. The high prevalence of AR negativity of TNBCs in AAs could explain observed worse outcomes and supports the existence of a unique subtype of Bca known as QNBC, worthy of scientific attention. Citation Format: Oluwadamilola Oladeru, Yasmine Kanaan, Tammy Naab, Luisel J. Ricks-Santi. Quadruple negative breast tumors in African American women express factors associated with worse prognosis compared to triple negative tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3682.
Among patients with triple-negative breast cancer (TNBC), several studies have suggested that der... more Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, ...
GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due t... more GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due to their robust and diffuse expression in mammary tissue. However, the expression of these markers has not been well characterized in tumors from African American women. The goal of this study was to characterize and evaluate the expression of GATA3 and mammaglobin breast tumors from African American women and determine their association with clinicopathological outcomes including breast cancer subtypes. Tissue microarrays (TMAs) were constructed from well preserved, morphologically representative tumors in archived formalin-fixed, paraffin-embedded (FFPE) surgical blocks from 202 patients with primary invasive ductal carcinoma. Mammaglobin, and GATA3 expression was assessed using immunohistochemistry (IHC). Univariate analysis was carried out to determine the association between expression of GATA3, mammaglobin and clinicopathological characteristics. Kaplan-Meier estimates of overall su...
Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR),... more Introduction: Quadruple negative breast cancer (QNBC) is defined by the absence of androgen (AR), estrogen (ER), progesterone (PR) receptors and human epidermal growth factor (HER2) expression. This subset of triple negative breast cancer (TNBC) has been described as unique to African American (AA) women and represents about 67-90% of all TNBC. Yet, there are limited clinical and therapeutic studies focused on this new subset of breast cancer (BCa) that is highly aggressive and portends a worse survival compared to AR positive Bca subtypes. The objectives of our study were to 1) determine the molecular and clinical characteristics of QNBC and compare them with other BCa subtypes and 2) determine the association of QNBC with clinicopathological factors and prognostic markers. Materials and Methods: Tissue arrays were constructed from FFPE tumor blocks of invasive ductal breast carcinomas in 202 AAs, diagnosed at Howard University from 2000 to 2010. Two separate tissue cores of IDC re...
Additional file 4: Table S3. Experimentally validated target genes of 33 selected miRNAs differen... more Additional file 4: Table S3. Experimentally validated target genes of 33 selected miRNAs differentially expressed in the three group comparisons. The Integrated Breast Cancer Pathway with miRNAs and experimentally validated target genes. Tumor size related miRs and target genes (pink), LN related miRs and target genes (orange), REC related miRs and target genes (blue), target genes associated with more than one comparison (green). Red lines represent inhibitory interaction, green lines represent stimulatory interaction, and black lines represent miRNA interaction with target.
1322 BRCA1/2 mutations were investigated in 99 independent families at elevated risk of germline ... more 1322 BRCA1/2 mutations were investigated in 99 independent families at elevated risk of germline mutations. Of the 99 high-risk families, 71 were families with multiple cases of breast cancer, 14 with multiple cases of breast and ovarian cancers, 8 with only early onset breast cancer (40 years or less), 3 with only bilateral breast cancer, 2 with male breast cancer, and 1 individual with breast and ovarian cancer. In this study, families were screened by denaturing high performance liquid chromatography (DHPLC). One deleterious BRCA1 mutation (5296delGAAA) was detected in two unrelated families. One of these families had 12 cases of breast cancer and 3 ovarian cancers, and the proband (tested individual) was diagnosed at age 32. The other family had 3 cases of breast cancer, 1 case of ovarian cancer, 2 cases of prostate cancer; and the proband was diagnosed at age 30 with estrogen/progesterone receptor-negative (ER-PR-) cancer. Early age of onset and ER-PR- tumors are characteristic...
Additional file 1: Table S1. Summary of the clinical and histopathological characteristics of the... more Additional file 1: Table S1. Summary of the clinical and histopathological characteristics of the TNBC-AA patients analyzed in this study.
Additional file 3: Table S2. MiRNAs that are significantly enriched and targets in Integrated Bre... more Additional file 3: Table S2. MiRNAs that are significantly enriched and targets in Integrated Breast Cancer Pathway in each clinical group evaluated. (P
Additional file 2: Figure S1. Principal Component Analysis (PCA) showing the clustering of the AA... more Additional file 2: Figure S1. Principal Component Analysis (PCA) showing the clustering of the AA patients (black dots) with the Africans, African Americans and African Caribbean groups based on genotype analysis. The horizontal axis represents Principal Component 1 (PC1) and vertical axis Principal Component 2 (PC2).
Additional file 5: Figure S2. The Integrated Breast Cancer Pathway with miRNAs and experimentally... more Additional file 5: Figure S2. The Integrated Breast Cancer Pathway with miRNAs and experimentally validated target genes. Tumor size related miRs and target genes (pink), LN related miRs and target genes (orange), REC related miRs and target genes (blue), target genes associated with more than one comparison (green). Red lines represent inhibitory interaction, green lines represent stimulatory interaction, and black lines represent miRNA interaction with target.
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