A Machine Learning Approach to Differentiate Two Specific Breast Cancer Subtypes Using Androgen Receptor Pathway Genes

Triple-negative breast cancer is a heterogeneous disease with different molecular and histological subtypes. The Androgen receptor is expressed in a portion of triple-negative breast cancer cases and the activation of the androgen receptor pathway is thought to be a molecular subtyping signature as well as a therapeutic target for triple-negative breast cancer. Thus, identification of the androgen receptor pathway status is important for both molecular characterization andclinical management. In this study, we investigate the expression of the androgen receptor pathway in metaplastic breast cancer and luminal androgen receptor subtypes of triple-negative breast cancer and found that the androgen receptor pathway was downregulated in metaplastic breast cancer compared to luminal androgen receptor subtype. Using random forest, we found that the two subtypes of breast cancer can be molecularly classified with the gene expression of the androgen receptor pathway.

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P-Rex1 Expression in Invasive Breast Cancer in relation to Receptor Status and Distant Metastatic Site

International Journal of Breast Cancer ◽

10.1155/2017/4537532 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 10

Author(s):

Jonathan D. Marotti ◽

Kristen E. Muller ◽

Laura J. Tafe ◽

Eugene Demidenko ◽

Todd W. Miller

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Breast Tumors ◽

Receptor Subtype ◽

Receptor Subtypes ◽

Solid Organ ◽

Breast Cancers ◽

Primary Tumors ◽

Receptor Status ◽

Cancer Subtypes

Background. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-Rex1) has been implicated in cancer growth, metastasis, and response to phosphatidylinositol 3-kinase (PI3K) inhibitor therapy. The aim of this study was to determine whether P-Rex1 expression differs between primary and metastatic human breast tumors and between breast cancer subtypes. Design. P-Rex1 expression was measured in 133 specimens by immunohistochemistry: 40 and 42 primary breast tumors from patients who did versus did not develop metastasis, respectively, and 51 breast-derived tumors from metastatic sites (36 of which had matching primary tumors available for analysis). Results. Primary breast tumors showed significant differences in P-Rex1 expression based on receptor subtype. ER+ and HER2+ primary tumors showed higher P-Rex1 expression than primary triple-negative tumors. HER2+ metastases from all sites showed significantly higher P-Rex1 expression compared to other metastatic receptor subtypes. Solid organ (i.e., brain, lung, and liver) metastases showed higher P-Rex1 expression compared to bone metastases. Conclusions. P-Rex1 expression is increased in ER+ and HER2+ breast cancers compared to triple-negative tumors. P-Rex1 may be differentially expressed in metastatic tumors based on site and receptor status. The role of P-Rex1 in the development of breast cancer metastases and as a predictive biomarker of therapeutic response warrants further investigation.

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Leucinostatins from Ophiocordyceps spp. and Purpureocillium spp. Demonstrate Selective Antiproliferative Effects in Cells Representing the Luminal Androgen Receptor Subtype of Triple Negative Breast Cancer

Journal of Natural Products ◽

10.1021/acs.jnatprod.0c00404 ◽

2020 ◽

Vol 83 (6) ◽

pp. 2010-2024

Author(s):

Yun-Seo Kil ◽

April L. Risinger ◽

Cora L. Petersen ◽

Susan L. Mooberry ◽

Robert H. Cichewicz

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Receptor Subtype ◽

Antiproliferative Effects ◽

In Cells

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Abstract P2-09-05: The potent anti-androgen enzalutamide demonstrates broad anti-tumour activity across all androgen receptor-positive triple-negative breast cancer subtypes

10.1158/0008-5472.sabcs13-p2-09-05 ◽

2013 ◽

Author(s):

L Denne ◽

A Shia ◽

E Komulainen ◽

V Haley ◽

C Lenihan ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Cancer Subtypes ◽

Anti Tumour Activity ◽

Tumour Activity

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Co-Expression of Androgen Receptor and Cathepsin D Defines a Triple-Negative Breast Cancer Subgroup with Poorer Overall Survival

Cancers ◽

10.3390/cancers12051244 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1244 ◽

Cited By ~ 3

Author(s):

Hanane Mansouri ◽

Lindsay B. Alcaraz ◽

Caroline Mollevi ◽

Aude Mallavialle ◽

William Jacot ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Cathepsin D ◽

Triple Negative ◽

Staining Intensity ◽

Macrophage Infiltration ◽

Receptor Subtype ◽

Breast Cancer Subgroup

Background: In the triple-negative breast cancer (TNBC) group, the luminal androgen receptor subtype is characterized by expression of androgen receptor (AR) and lack of estrogen receptor and cytokeratin 5/6 expression. Cathepsin D (Cath-D) is overproduced and hypersecreted by breast cancer (BC) cells and is a poor prognostic marker. We recently showed that in TNBC, Cath-D is a potential target for antibody-based therapy. This study evaluated the frequency of AR/Cath-D co-expression and its prognostic value in a large series of patients with non-metastatic TNBC. Methods: AR and Cath-D expression was evaluated by immunohistochemistry in 147 non-metastatic TNBC. The threshold for AR positivity (AR+) was set at ≥1% of stained cells, and the threshold for Cath-D positivity (Cath-D+) was moderate/strong staining intensity. Lymphocyte density, macrophage infiltration, PD-L1 and programmed cell death (PD-1) expression were assessed. Results: Scarff-Bloom-Richardson grade 1–2 and lymph node invasion were more frequent, while macrophage infiltration was less frequent in AR+/Cath-D+ tumors (62.7%). In multivariate analyses, higher tumor size, no adjuvant chemotherapy and AR/Cath-D co-expression were independent prognostic factors of worse overall survival. Conclusions: AR/Cath-D co-expression independently predicted overall survival. Patients with TNBC in which AR and Cath-D are co-expressed could be eligible for combinatory therapy with androgen antagonists and anti-Cath-D human antibodies.

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Identification of new therapeutic leads for triple negative breast cancer subtypes

Planta Medica ◽

10.1055/s-0035-1556254 ◽

2015 ◽

Vol 81 (11) ◽

Author(s):

AJ Robles ◽

L Du ◽

S Cai ◽

RH Cichewicz ◽

SL Mooberry

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Cancer Subtypes ◽

Therapeutic Leads

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Androgen receptor expression in triple-negative breast cancer

10.26226/morressier.596cd2b6d462b80292387085 ◽

2017 ◽

Author(s):

Ievgen Glavynskyi

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Receptor Expression ◽

Androgen Receptor Expression

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Faculty Opinions recommendation of Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13405017.14775138 ◽

2011 ◽

Author(s):

Thomas Egelhoff

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Targeted Therapies ◽

Triple Negative ◽

Breast Cancer Subtypes ◽

Preclinical Models ◽

Cancer Subtypes ◽

Selection Of

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Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000443052 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1003-1014 ◽

Cited By ~ 24

Author(s):

Aiyu Zhu ◽

Yan Li ◽

Wei Song ◽

Yumei Xu ◽

Fang Yang ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Cyclin D1 ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

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