Gene Expression Signature of Normal Cell-of-Origin Predicts Ovarian Tumor Outcomes

Merritt, Melissa A.; Bentink, Stefan; Schwede, Matthew; Iwanicki, Marcin P.; Quackenbush, John; Woo, Terri; Agoston, Elin S.; Reinhardt, Ferenc; Crum, Christopher P.; Berkowitz, Ross S.; Mok, Samuel C.; Witt, Abigail E.; Jones, Michelle; Wang, Bin; Ince, Tan A.

doi:10.1371/journal.pone.0080314

Cited by 43 publications

(61 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These experiments identified a broad correlation between high HDAC7 protein expression with a variety of well-established CSC markers (Figure 3e, Supplementary Figure 10d). These results were also confirmed in tumour cells freshly isolated from seven primary human ovarian and breast cancers, 30 and in formalin-fixed paraffin-embedded sections of primary human breast cancer tissues (Supplementary Figure 11). In sum, we observed a correlation between eight CSC markers and high HDAC7 protein expression in seven cell lines and seven primary tumours using IF staining.…”

Section: Resultssupporting

confidence: 60%

Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

et al. 2016

View full text Add to dashboard Cite

Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.

show abstract

Section: Resultssupporting

confidence: 60%

Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

et al. 2016

View full text Add to dashboard Cite

show abstract

“…For example, we previously demonstrated that while some normal cell types gave rise to highly tumorigenic and metastatic adenocarcinomas, other breast cell types that were isolated from the same patient and transformed with identical oncogenes gave rise to cells that were morphologically distinct, weakly tumorigenic, and nonmetastatic (16,(47)(48)(49). Others have also suggested that the same oncogenes can have vastly different phenotypic consequences depending on the cell of origin (50,51).…”

Section: Discussionmentioning

confidence: 99%

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Santagata¹,

Thakkar²,

Ergonul³

et al. 2014

J. Clin. Invest.

Self Cite

171

214

View full text Add to dashboard Cite

Accurate classification is essential for understanding the pathophysiology of a disease and can inform therapeutic choices. For hematopoietic malignancies, a classification scheme based on the phenotypic similarity between tumor cells and normal cells has been successfully used to define tumor subtypes; however, use of normal cell types as a reference by which to classify solid tumors has not been widely emulated, in part due to more limited understanding of epithelial cell differentiation compared with hematopoiesis. To provide a better definition of the subtypes of epithelial cells comprising the breast epithelium, we performed a systematic analysis of a large set of breast epithelial markers in more than 15,000 normal breast cells, which identified 11 differentiation states for normal luminal cells. We then applied information from this analysis to classify human breast tumors based on normal cell types into 4 major subtypes, HR0-HR3, which were differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression. Examination of 3,157 human breast tumors revealed that these HR subtypes were distinct from the current classification scheme, which is based on estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when they expressed none of the receptors (subtype HR0). Together, these data provide an ontological classification scheme associated with patient survival differences and provides actionable insights for treating breast tumors.

show abstract

“…Primary fallopian tube secretory epithelial cells (FTECs) were isolated61 and cultured62 as previously described.…”

Section: Methodsmentioning

confidence: 99%

Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status

et al. 2016

View full text Add to dashboard Cite

A cell line representative of human high-grade serous ovarian cancer (HGSOC) should not only resemble its tumour of origin at the molecular level, but also demonstrate functional utility in pre-clinical investigations. Here, we report the integrated proteomic analysis of 26 ovarian cancer cell lines, HGSOC tumours, immortalized ovarian surface epithelial cells and fallopian tube epithelial cells via a single-run mass spectrometric workflow. The in-depth quantification of >10,000 proteins results in three distinct cell line categories: epithelial (group I), clear cell (group II) and mesenchymal (group III). We identify a 67-protein cell line signature, which separates our entire proteomic data set, as well as a confirmatory publicly available CPTAC/TCGA tumour proteome data set, into a predominantly epithelial and mesenchymal HGSOC tumour cluster. This proteomics-based epithelial/mesenchymal stratification of cell lines and human tumours indicates a possible origin of HGSOC either from the fallopian tube or from the ovarian surface epithelium.

show abstract

Gene Expression Signature of Normal Cell-of-Origin Predicts Ovarian Tumor Outcomes

Cited by 43 publications

References 59 publications

Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

Taxonomy of breast cancer based on normal cell phenotype predicts outcome

Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status

Contact Info

Product

Resources

About