Abstract 3663: A gene signature for predicting outcome in patients with basal-like breast cancer

AbstractCancers evade the immune system in order to grow or metastasise through the process of cancer immunoediting. While checkpoint inhibitor therapy has been effective for reactivating tumour immunity in some cancers, many solid cancers, including breast cancer, remain largely non-responsive. Understanding the way non-responsive cancers evolve to evade immunity, what resistance pathways are activated and whether this occurs at the clonal level will improve immunotherapeutic design. We tracked cancer cell clones during the immunoediting process and determined clonal transcriptional profiles that allow immune evasion in murine mammary tumour growth in response to immunotherapy with anti-PD1 and anti-CTLA4. Clonal diversity was significantly restricted by immunotherapy treatment at both the primary and metastatic sites. These findings demonstrate that immunoediting selects for pre-existing breast cancer cell populations, that immunoediting is not a static process and is ongoing during metastasis and immunotherapy treatment. Isolation of immunotherapy resistant clones revealed unique and overlapping transcriptional signatures. The overlapping gene signature was predictive of poor survival in basal-like breast cancer patient cohorts. Some of these overlapping genes have existing small molecules which can be used to potentially improve immunotherapy response.

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Role of FOXC1 in regulation of basal-like/triple-negative breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.11016 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 11016-11016 ◽

Cited By ~ 1

Author(s):

P. S. Ray ◽

J. Wang ◽

Y. Qu ◽

M. Shin-Sim ◽

J. Shamonki ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Gene Signature ◽

Normal Breast ◽

Basal Like Breast Cancer ◽

Breast Epithelial

11016 Background: Class identification studies have proposed 3 prognostically relevant molecular subtypes of breast cancer: luminal, HER2 and basal-like. The latter is associated with poor prognosis but its molecular basis is not clear. We hypothesized a direct correlation between FOXC1 expression and basal-like breast cancer. Methods: Expression of FOXC1, CK5, CK14, EGFR, c-Kit, αB-crystallin, ITGB4 and FOXC2 in basal-like breast cancer was examined using publicly available microarray datasets. A molecular signature of 40 genes sharing co-ordinate up or down regulation with FOXC1 was identified on one microarray (49 patients) and validated on 5 other microarrays (1,232 patients). The clinical significance of FOXC1 gene expression and the FOXC1 gene signature was evaluated using censored survival data. FOXC1 protein expression was assessed by immunohistochemistry (IHC) of a 96-sample breast cancer tissue microarray. Normal breast epithelial, luminal and basal breast cancer cells transfected with FOXC1 vectors were evaluated for cell proliferation, migration and invasion. Results: FOXC1 was found to be consistently and exclusively upregulated in basal-like triple negative breast cancer and was associated with poor overall survival (p<0.0001). The FOXC1 gene signature accurately predicted the basal-like phenotype. IHC analysis of FOXC1 protein expression in human breast cancers confirmed its potential to be used as a clinical biomarker of basal-like breast cancer. Normal breast epithelial cells and luminal breast cancer cells with low or no FOXC1 expression underwent epithelial-to-mesenchymal transition and displayed increased cellular proliferation, migration, invasion, and expression of basal cell markers when FOXC1 was overexpressed. In contrast, knockdown of FOXC1 by shRNA in basal-like breast cancer cells conferred luminal phenotype. Breast cancer progression-linked signaling pathways like NF-κB and p38MAPK were significantly stimulated in basal-like breast cancer as well as by in vitro FOXC1 overexpression. Conclusions: FOXC1 is a dominant determinant of the basal-like phenotype of breast cancer. We propose FOXC1 to be the single best molecular marker of and a potential therapeutic target for basal-like / triple negative breast cancer. No significant financial relationships to disclose.

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Gene expression-based predictors of chemotherapy response in basal-like breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10500 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10500-10500 ◽

Cited By ~ 2

Author(s):

Aleix Prat ◽

Ana Lluch ◽

Joan Albanell ◽

Cheng Fang ◽

Jose Ignacio Chacon Lopez-Muniz ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Gene Signature ◽

High Expression ◽

Chemotherapy Response ◽

Biological Processes ◽

Expression Of Genes ◽

Basal Like Breast Cancer

10500 Background: The Basal-like subtype is generally associated with high chemo-sensitivity, but not all tumors respond and/or benefit to the same extend. In this study, we sought to identify gene expression predictors of neoadjuvant chemotherapy sensitivity in Basal-like breast cancer. Methods: Expression of 542 genes was measured using the Nanostring nCounter platform from 69 FFPE pre-treated samples of the GEICAM/2006-03 phase II trial, which were treated with epirrubicin/cyclophosphamide followed by docetaxel+/-carboplatin. Research-based PAM50 and Claudin-low predictors were also evaluated. The association between response (Miller-Payne criteria) and gene/signature expression was assessed by multivariable ordinal logistic regression. Significant findings were evaluated in 109 independent triple-negative and Basal-like tumors treated with anthracycline/taxane-based chemotherapy (Hatzis et al.). Finally, interaction tests were performed to identify genes/signatures associated with carboplatin response. Results: In GEICAM/2006-03, 61/69 (88%) tumors were identified as Basal-like by PAM50. High correlation to the Basal-like centroid, or high expression of proliferation-related genes (i.e. FANCA), were found to be significantly associated with high chemo-sensitivity, whereas high expression of genes associated with mesenchymal/stem cell biological processes (i.e. SNAI1 and IL6) and/or luminal differentiation (i.e. MUC1 and FOXA1) were significantly associated with chemo-resistance; similar findings were observed in Hatzis et al. Finally, high expression of genes associated with proliferation/DNA-repair (i.e. ATR) and tight junctions (i.e. CLDN3/4/7) were found associated with carboplatin response, whereas expression of the Claudin-low signature was found associated with carboplatin resistance. Conclusions: High expression of Basal-like and/or proliferation-related genes and low expression of luminal/mesenchymal/stem cell-like biological processes were consistently identified as predictive of chemotherapy response. Our data suggests that gene expression profiling might help shed light into the biological and clinical heterogeneity of Basal-like breast cancer.

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Development and validation of prognostic gene signature for basal-like breast cancer and high-grade serous ovarian cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-020-05884-z ◽

2020 ◽

Vol 184 (3) ◽

pp. 689-698

Author(s):

Yi Zhang ◽

Jianfang Liu ◽

Praveen-Kumar Raj-Kumar ◽

Lori A. Sturtz ◽

Anupama Praveen-Kumar ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Gene Signature ◽

High Grade ◽

Serous Ovarian Cancer ◽

Prognostic Gene ◽

Prognostic Gene Signature ◽

Basal Like Breast Cancer ◽

Development And Validation

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A Histone Acetylation Modulator Gene Signature for Classification and Prognosis of Breast Cancer

Current Oncology ◽

10.3390/curroncol28010091 ◽

2021 ◽

Vol 28 (1) ◽

pp. 928-939

Author(s):

Mengping Long ◽

Wei Hou ◽

Yiqiang Liu ◽

Taobo Hu

Keyword(s):

Breast Cancer ◽

Histone Acetylation ◽

Molecular Subtypes ◽

Gene Signature ◽

Data Sources ◽

Differentially Expressed ◽

Breast Cancers ◽

Acetylation Level ◽

Close Relationship ◽

Basal Like Breast Cancer

Regulators of histone acetylation are promising epigenetic targets for therapy in breast cancer. In this study, we comprehensively analyzed the expression of histone acetylation modulator genes in breast cancer using TCGA data sources. A gene signature composed of eight histone acetylation modulators (HAMs) was found to be effective for the classification and prognosis of breast cancers, especially in the HER2-enriched and basal-like molecular subtypes. The eight genes consist of two histone acetylation writers (GTF3C4 and CLOCK), two erasers (HDAC2 and SIRT7) and four readers (BRD4, BRD7, SP100, and BRWD3). Both histone acetylation writer genes and eraser genes were found to be differentially expressed between the two groups indicating a close relationship exists between overall histone acetylation level and prognosis of breast cancer in HER2-enriched and basal-like breast cancer.

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