Dissecting the Biological Heterogeneity within Hormone Receptor Positive HER2 Negative Breast Cancer by Gene Expression Markers Identifies Indolent Tumors within Late Stage Disease

Prabhu, Jyothi S; Korlimarla, Aruna; Anupama, C E; Alexander, A.; Raghavan, Rohini; Kaul, Roma; Desai, Krisha; Rajarajan, Savitha; Manjunath, Suraj; Correa, Marjorie; Raman, Rohini; Kalamdani, Anjali; Prasad, Msn; Patil, Shekar; Gopinath, K. S.; Srinath, B S; Sridhar, T.S.

doi:10.1016/j.tranon.2017.04.011

Cited by 10 publications

(17 citation statements)

References 38 publications

(56 reference statements)

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“…1,3 Although many luminal-A tumors are highly responsive to endocrine therapies like tamoxifen, a significant proportion possess intrinsic and/or acquired resistance. 4,5 Even this relatively well-characterized breast cancer subtype possesses heterogeneity at the levels of hormone receptor expression, 6,7 treatment response, 5 and genetic variability 2,3 that requires further understanding.…”

Section: Introductionmentioning

confidence: 99%

Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses

et al. 2019

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Breast cancer is a highly heterogeneous disease. Although differences between intrinsic breast cancer subtypes have been well studied, heterogeneity within each subtype, especially luminal-A cancers, requires further interrogation to personalize disease management. Here, we applied well-characterized and cancer-associated heterocellular signatures representing stem, mesenchymal, stromal, immune, and epithelial cell types to breast cancer. This analysis stratified the luminal-A breast cancer samples into five subtypes with a majority of them enriched for a subtype (stem-like) that has increased stem and stromal cell gene signatures, representing potential luminal progenitor origin. The enrichment of immune checkpoint genes and other immune cell types in two (including stem-like) of the five heterocellular subtypes of luminal-A tumors suggest their potential response to immunotherapy. These immune-enriched subtypes of luminal-A tumors (containing only estrogen receptor positive samples) showed good or intermediate prognosis along with the two other differentiated subtypes as assessed using recurrence-free and distant metastasis-free patient survival outcomes. On the other hand, a partially differentiated subtype of luminal-A breast cancer with transit-amplifying colon-crypt characteristics showed poor prognosis. Furthermore, published luminal-A subtypes associated with specific somatic copy number alterations and mutations shared similar cellular and mutational characteristics to colorectal cancer subtypes where the heterocellular signatures were derived. These heterocellular subtypes reveal transcriptome and cell-type based heterogeneity of luminal-A and other breast cancer subtypes that may be useful for additional understanding of the cancer type and potential patient stratification and personalized medicine.

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Section: Introductionmentioning

confidence: 99%

Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses

et al. 2019

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“…Breast cancers are usually classified into estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-positive (HER2+), or triple-negative breast cancer (TNBC) [3]. About 20% of breast cancers are an overexpression of HER2, a gene correlated with more aggression compared with other subtypes [4, 5]. Despite advances in the treatment of patients with this disease, it is often accompanied by poor prognosis of patients [6].…”

Section: Introductionmentioning

confidence: 99%

AK4 Promotes the Progression of HER2-Positive Breast Cancer by Facilitating Cell Proliferation and Invasion

Zhang

Yin

et al. 2019

Disease Markers

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Breast cancer (BC) is a type of malignant tumor originating from the epithelial tissue of the mammary gland, and about 20% of breast cancers are human epidermal growth factor receptor 2 positive (HER2+), which is a subtype with more aggression. Recently, HER2-positive breast cancer is often accompanied by poor prognosis of patients, and targeted therapy showed a promising prospect. To combat this disease, novel therapeutic targets are still needed. Adenylate kinase 4 (AK4) is a member of the adenylate kinase family and is expressed in the mitochondrial matrix. AK4 is involved in multiple cellular functions such as energy metabolism homeostasis. Interestingly, AK4 was observed highly expressed in several tumor tissues, and the involvement of AK4 in cancer development was generally revealed. However, the possible role of AK4 on the growth and development of breast cancer is still unclear. Here, we investigated the possible functions of AK4 on the progression of HER2-positive breast cancer. We found the high expression of AK4 in HER2-positive breast cancer tissues from patients who received surgical treatment. Additionally, AK4 expression levels were obviously correlated with clinical-pathological features, including pTNM stage (P = 0.017) and lymph node metastasis (P = 0.046). We mechanically confirmed that AK4 depletion showed the obvious impairment of cell proliferation and invasion in MCF7 and MDA-MB-231 cells. AK4 also facilitates tumor growth and metastasis of HER2-positive breast cancer in vivo. In conclusion, we identified and mechanically confirmed that AK4 is a novel therapeutic target of HER2-positive breast cancer.

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“…We used 4 gene signatures to score the individual patient samples to characterize their luminal, basal, epithelial and mesenchymal characteristics. The gene lists for the luminal and basal signature were obtained from a cumulative list of genes (Supplementary Table S4) listed from previously published reports (13)(14)(15)(16)(17) and the gene lists for the epithelial and mesenchymal programs were obtained from Tan et al, EMBO Mol. Med.…”

Section: Computational Analysis For Correlation With E/m Hybrid Scorementioning

confidence: 99%

“…Table 1 -List of miR-18a targets: Target scan analysis was performed to decipher the gene targets of miR-18a. 15 targets identified by at least 3 different target mining softwares and their known function are enlisted below.…”

Section: Tablesmentioning

confidence: 99%

Acquisition of hybrid E/M phenotype associated with increased migration, drug resistance and stemness is mediated by reduced miR-18a levels in ER-negative breast cancer

Nair

Apoorva

Chandrakala

et al. 2022

Preprint

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The complexity of the ER-negative subtype of breast cancer arises due to the heterogeneous nature of the disease rendering them more aggressive and this poses a challenge to effective treatment and eventually the prognosis of the patients. We have explored the miRNA regulation of altered molecular signatures and the effect on tumour progression in ER-negative breast cancer. Using breast tumour specimens, gene expression data from public datasets and in-vitro and in-vivo model systems we have shown that low-levels of miR-18a in ER-negative tumours drives enrichment of hybrid Epithelial/Mesenchymal (E/M) cells with luminal attributes. On inhibition of miR-18a in ER-negative breast cancer cell lines, the cells showed traits of increased migration, stemness and drug-resistance. miR-18a/low tumours were also associated with increased expression of genes associated with EMT, stemness, drug resistance and immune-suppression. Further analysis of the miR-18a targets pointed out at a possible HIF-1α mediated signalling in these tumours. HIF-1α inhibition reduced the enrichment of the hybrid E/M cells and decreased the migratory ability of miR-18a/low cells. Our study reports for the first time a dual role of miR-18a in breast cancer that is subtype specific based on hormone receptor expression and a novel association of low miR-18a levels and enrichment of hybrid E/M cells. The results highlight the possibility of stratifying the ER-negative disease into clinically relevant groups by analysing epigenetic signatures.

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Dissecting the Biological Heterogeneity within Hormone Receptor Positive HER2 Negative Breast Cancer by Gene Expression Markers Identifies Indolent Tumors within Late Stage Disease

Cited by 10 publications

References 38 publications

Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses

Heterocellular gene signatures reveal luminal-A breast cancer heterogeneity and differential therapeutic responses

AK4 Promotes the Progression of HER2-Positive Breast Cancer by Facilitating Cell Proliferation and Invasion

Acquisition of hybrid E/M phenotype associated with increased migration, drug resistance and stemness is mediated by reduced miR-18a levels in ER-negative breast cancer

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