Estrogen Receptor Positive Breast Cancer with High Expression of Androgen Receptor has Less Cytolytic Activity and Worse Response to Neoadjuvant Chemotherapy but Better Survival

Okano, Maiko; Oshi, Masanori; Butash, Ali; Asaoka, Mariko; Katsuta, Eriko; Peng, Xuan; Qi, Qianya; Li, Yan; Takabe, Kazuaki

doi:10.3390/ijms20112655

Cited by 59 publications

(56 citation statements)

References 44 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Normalized microarray-based tumor gene expression and clinical data for 1903 patients of METABRIC cohort were obtained through the cBio portal, as we previously reported [48][49][50]. For the following studies, normalized microarray-based tumor gene expression and clinical data were obtained from Gene Expression Omnibus (GEO) repository (http://www.ncbi.nlm.ih.gov/geo/): Shi et al…”

Section: Data Of Metabric and Other Breast Cancer Cohortsmentioning

confidence: 99%

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Oshi

Takahashi

Tokumaru

et al. 2020

IJMS

Self Cite

109

107

View full text Add to dashboard Cite

The vast majority of breast cancer death is a result of metastasis. Thus, accurate identification of patients who are likely to have metastasis is expected to improve survival. The G2M checkpoint plays a critical role in cell cycle. We hypothesized that breast cancer tumors with high activity of G2M pathway genes are more aggressive and likely to metastasize. To test this, we used the single-sample gene set variation analysis method to calculate the score for the Hallmark G2M checkpoint pathway using gene expression data of a total of 4626 samples from 12 human breast cancer cohorts. As expected, a high G2M pathway score correlated with enriched tumor expression of other cell proliferation-related gene sets. The score was significantly associated with clinical aggressive features of tumors and patient survival in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Interestingly, a high G2M score of metastasis tumors was also significantly associated with worse survival. In primary as well as metastasis tumors with high scores, the infiltration of both pro- and anti-cancerous immune cells increased. Tumor G2M score was also associated with treatment response to systemic chemotherapy in ER-positive/HER2-negative cancer, and was predictive of response to cyclin-dependent kinase inhibition therapy.

show abstract

Section: Data Of Metabric and Other Breast Cancer Cohortsmentioning

confidence: 99%

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Oshi

Takahashi

Tokumaru

et al. 2020

IJMS

Self Cite

109

107

View full text Add to dashboard Cite

show abstract

“…GSEA was performed comparing the high mutation and low mutation tumors, utilizing the Hallmark gene sets 38 with the software provided by the Broad Institute (https:// software.broadinstitute.org/gsea/index.jsp), as described before 20,21,24,39 .…”

Section: Gene Set Enrichment Analysis (Gsea)mentioning

confidence: 99%

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

Takahashi

Asaoka

Yan

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRnA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs. Accumulation of somatic mutations, or somatic genome instability, has been the principle of carcinogenesis; cancer cells stem from a clone that has gained the somatically acquired genetic abnormalities, leading to malignant transformation and further progression 1. With advances in next-generation sequencing technologies, clinical interest in assessing mutation burden and identifying specific mutations in certain cancer types has been growing to utilize targeted therapies or to assess tumor biology, such as FoundationOne genomic panel testing 2-4. Mutation rates are variable among cancer types and outliers with significantly high mutation burdens, hypermutation, do exist in many cancer types 5. Interestingly, the definition of hypermutation has been variable in the literature 5-7 , although the common definition is usually greater than 10-100 mutations per Mega base pairs (Mbps). Campbell and colleagues recently performed comprehensive analysis of hypermutation in various tumor types, providing more insight into tumor evolution and identifying possible clinically actionable mutation signatures 6. The etiology of hypermutation varies between cancer types; ultraviolet (UV) light is the significant cause of mutations in melanoma, while smoking causes the mutations in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (SCC) 7,8. Whereas UV light and smoking are examples of exogenous mutagens, there are endogenous processes for mutation, such as microsatellite instability (MSI), and Apolipoprotein

show abstract

“…A meta-analysis by Bozovic-Spasojevic et al employing univariate and multivariate analyses, uncovered that AR expression results in significantly improved disease-free survival (DFS) and OS in ER+ BCs ( 44 ). In one study using transcriptomic data obtained from TCGA and METABRIC cohorts, high AR levels in ER+ BC correlated with fewer tumor-infiltrating lymphocytes and cytolytic activity, as well as far less sensitivity to neoadjuvant chemotherapy, yet better survival ( 45 ). However, a study of 3,021 postmenopausal women with early-stage ER+ BC showed that AR expression was not linked with the prognosis, nor could it predict the response to letrozole or tamoxifen ( 46 ).…”

Section: The Clinical Relevance Of Ar In Bcmentioning

confidence: 99%

Androgen Receptor in Breast Cancer: From Bench to Bedside

Chen

Yang

et al. 2020

Front. Endocrinol.

View full text Add to dashboard Cite

Breast cancer (BC) is one of the most common malignancies and the leading cause of cancer-related mortality in women. Androgen receptor (AR) is frequently expressed in diverse BC subtypes. Accumulating evidence has revealed that AR might be a predictive or prognostic factor and a drug target in BC. AR expression and AR pathways differ in various BC subtypes, thereby resulting in controversial inferences on the predictive and prognostic value of AR. Herein, we summarized the roles of AR in different BC subtypes and AR-targeting therapies based on preclinical and clinical studies. Moreover, we highlighted the possible efficacy of a combination therapy via exploiting the AR-related mechanisms and the research on therapeutic resistance.

show abstract

Estrogen Receptor Positive Breast Cancer with High Expression of Androgen Receptor has Less Cytolytic Activity and Worse Response to Neoadjuvant Chemotherapy but Better Survival

Cited by 59 publications

References 44 publications

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

G2M Cell Cycle Pathway Score as a Prognostic Biomarker of Metastasis in Estrogen Receptor (ER)-Positive Breast Cancer

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

Androgen Receptor in Breast Cancer: From Bench to Bedside

Contact Info

Product

Resources

About