Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Breast Cancer Res Treat. 2020 Jan;179(1):25-35. doi: 10.1007/s10549-019-05419-1. Epub 2019 Sep 17.
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.
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.
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 (χ = 12.07; P = 0.002) and advanced nuclear grade (χ = 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.
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.
高迁移率族蛋白 A1（HMGA1）染色质重塑蛋白是临床前乳腺癌模型中转移进展和癌症干细胞特性所必需的，尽管其在乳腺癌发生中的作用仍不清楚。为了研究原发性乳腺癌中的 HMGA1，我们评估了来自一大群亚洲女性的肿瘤中的免疫反应评分（IRS）；从两个独立的西方队列中查询了 HMGA1 基因表达。
从韩国女性的乳腺癌肿瘤中产生 HMGA1 IRS，作为染色强度（弱=1，中=2，强=3）和阳性细胞百分比（<5%=0，5-30%=1，30-60%=2，>60%=3）的乘积，并分为三组：低（<3），中（3-6），高（>6）。我们从两个大型数据库（TCGA、METABRIC）评估了 HMGA1 和雌激素受体（ESR1）基因表达。从 METABRIC 队列中确定了总生存期。
在来自韩国女性的 540 例原发性肿瘤中（181 例 ER 阴性，359 例 ER 阳性），HMGA1 IRS<3 的有 89 例（16.5%），3-6 的有 215 例（39.8%），>6 的有 236 例（43.7%）。高 HMGA1 IRS 与雌激素受体（ER）阴性（χ2=12.07；P=0.002）和高级核级（χ2=12.83；P=0.012）相关。在两个大型西方队列中，与非恶性乳腺组织相比，HMGA1 基因在乳腺癌中过度表达（P<0.0001），包括亚洲人、非裔美国人和白种人亚组。HMGA1 在 ER 阴性肿瘤中最高，并且 HMGA1 和 ESR1 基因表达之间存在很强的负相关（Pearson r=-0.60，P<0.0001）。最重要的是，高 HMGA1 预测所有乳腺癌女性的总生存期降低（P<0.0001），并进一步将 ER 阳性肿瘤分为预后较差的肿瘤。
总之，我们的结果表明 HMGA1 有助于雌激素独立性、肿瘤进展和不良结局。此外，需要进一步研究以确定 HMGA1 是否可以作为乳腺癌女性的预后标志物和治疗靶点。
