Mikhail Gorbounov1, Neil M Carleton2, Rebecca J Asch-Kendrick1, Lingling Xian3, Lisa Rooper1, Lionel Chia1,3,4, Ashley Cimino-Mathews1,5, Leslie Cope5,6, Alan Meeker1,2,5, Vered Stearns5, Robert W Veltri2, Young Kyung Bae7, Linda M S Resar8,9,10,11,12,13. 1. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 2. Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 3. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 4. Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 5. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 6. Department of Biostatistics, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. 7. Department of Pathology, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu, 42415, South Korea. ykbae@ynu.ac.kr. 8. Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lresar@jhmi.edu. 9. Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lresar@jhmi.edu. 10. Pathobiology Graduate Program, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lresar@jhmi.edu. 11. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lresar@jhmi.edu. 12. Institute for Cellular Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lresar@jhmi.edu. 13. The Johns Hopkins University School of Medicine, Ross Research Building, Room 1025, 720 Rutland Ave, Baltimore, MD, 21205, USA. lresar@jhmi.edu.
Abstract
PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.
PURPOSE: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts. METHODS: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort. RESULTS: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ2 = 12.07; P = 0.002) and advanced nuclear grade (χ2 = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes. CONCLUSIONS: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.
Entities:
Keywords:
Breast cancer; ER-negative; HMGA1; High mobility group A1 chromatin remodeling proteins; Tumor progression
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