High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer

Mikhail Gorbounov, Neil M. Carleton, Rebecca J. Asch-Kendrick, Lingling Xian, Lisa Rooper, Lionel Chia, Ashley Cimino-Mathews, Leslie Cope, Alan Meeker, Vered Stearns, Robert W. Veltri, Young Kyung Bae, Linda M.S. Resar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jan 1 2019

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High Mobility Group Proteins
Estrogen Receptors
Breast Neoplasms
Gene Expression
Neoplasms
Breast
Estrogen Receptor beta
Chromatin Assembly and Disassembly
Asian Americans
Survival
Neoplastic Stem Cells
African Americans
Estrogens
Carcinogenesis
Databases
Staining and Labeling
Genes

Keywords

  • Breast cancer
  • ER-negative
  • High mobility group A1 chromatin remodeling proteins
  • HMGA1
  • Tumor progression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer. / Gorbounov, Mikhail; Carleton, Neil M.; Asch-Kendrick, Rebecca J.; Xian, Lingling; Rooper, Lisa; Chia, Lionel; Cimino-Mathews, Ashley; Cope, Leslie; Meeker, Alan; Stearns, Vered; Veltri, Robert W.; Bae, Young Kyung; Resar, Linda M.S.

In: Breast Cancer Research and Treatment, 01.01.2019.

Research output: Contribution to journalArticle

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title = "High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer",
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.",
keywords = "Breast cancer, ER-negative, High mobility group A1 chromatin remodeling proteins, HMGA1, Tumor progression",
author = "Mikhail Gorbounov and Carleton, {Neil M.} and Asch-Kendrick, {Rebecca J.} and Lingling Xian and Lisa Rooper and Lionel Chia and Ashley Cimino-Mathews and Leslie Cope and Alan Meeker and Vered Stearns and Veltri, {Robert W.} and Bae, {Young Kyung} and Resar, {Linda M.S.}",
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journal = "Breast Cancer Research and Treatment",
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T1 - High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer

AU - Gorbounov, Mikhail

AU - Carleton, Neil M.

AU - Asch-Kendrick, Rebecca J.

AU - Xian, Lingling

AU - Rooper, Lisa

AU - Chia, Lionel

AU - Cimino-Mathews, Ashley

AU - Cope, Leslie

AU - Meeker, Alan

AU - Stearns, Vered

AU - Veltri, Robert W.

AU - Bae, Young Kyung

AU - Resar, Linda M.S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - ER-negative

KW - High mobility group A1 chromatin remodeling proteins

KW - HMGA1

KW - Tumor progression

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