The Secreted Protein C10orf118 Is a New Regulator of Hyaluronan Synthesis Involved in Tumour-Stroma Cross-Talk

Interaction between cancer cells and their microenvironment is central in defining the fate of cancer development. Tumour cells secrete signals (cytokines, chemokines, growth factors) that modify the surrounding area, while the niche supplies structures and activities necessary for tumour maintenance and growth. Hyaluronan (HA) is a glycosaminoglycan that constitute cancer cell niche and is known to influence tumour functions such as proliferation, migration and neoangiogenesis. The knowledge of the factors regulating HA synthesis and size is crucial in understanding the mechanisms sustaining tumour development. Here we show that a yet uncharacterized protein secreted by breast tumour cell lines, named c10orf118 (accession number NM_018017 in NCBI/BLAST, and Q7z3E2 according to the Uniprot identifier), with a predicted length of 898 amino acids, can induce the secretion of HA by stromal fibroblasts through the up-regulation of the hyaluronan synthase 2 gene (HAS2). Intracellularly, this protein is localized in the Golgi apparatus with a possible role in vesicle maturation and transport. The expression of c10orf118 was verified in breast cancer patient specimens and was found to be associated with the presence of estrogen receptor that characterizes a good patient survival. We suggest c10orf118 as a new player that influences the HA amount in breast cancer microenvironment and is associated with low aggressiveness of cancer.

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Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance

Endocrine Related Cancer ◽

10.1530/erc-17-0139 ◽

2017 ◽

Vol 24 (10) ◽

pp. R349-R366 ◽

Cited By ~ 19

Author(s):

Catherine Zabkiewicz ◽

Jeyna Resaul ◽

Rachel Hargest ◽

Wen Guo Jiang ◽

Lin Ye

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Therapeutic Potential ◽

Current Knowledge ◽

Breast Tumour ◽

Cellular Functions ◽

Foetal Development ◽

Key Factor ◽

The Right

Bone morphogenetic proteins (BMPs) belong to the TGF-β super family, and are essential for the regulation of foetal development, tissue differentiation and homeostasis and a multitude of cellular functions. Naturally, this has led to the exploration of aberrance in this highly regulated system as a key factor in tumourigenesis. Originally identified for their role in osteogenesis and bone turnover, attention has been turned to the potential role of BMPs in tumour metastases to, and progression within, the bone niche. This is particularly pertinent to breast cancer, which commonly metastasises to bone, and in which studies have revealed aberrations of both BMP expression and signalling, which correlate clinically with breast cancer progression. Ultimately a BMP profile could provide new prognostic disease markers. As the evidence suggests a role for BMPs in regulating breast tumour cellular function, in particular interactions with tumour stroma and the bone metastatic microenvironment, there may be novel therapeutic potential in targeting BMP signalling in breast cancer. This review provides an update on the current knowledge of BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis.

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Down-Regulation of the Proteoglycan Decorin Fills in the Tumor-Promoting Phenotype of Ionizing Radiation-Induced Senescent Human Breast Stromal Fibroblasts

Cancers ◽

10.3390/cancers13081987 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1987

Author(s):

Eleni Mavrogonatou ◽

Adamantia Papadopoulou ◽

Asimina Fotopoulou ◽

Stathis Tsimelis ◽

Heba Bassiony ◽

...

Keyword(s):

Breast Cancer ◽

Ionizing Radiation ◽

Cancer Progression ◽

Breast Cancer Cell Lines ◽

Phenotypic Trait ◽

Mrna Levels ◽

Human Breast ◽

Down Regulation ◽

Stromal Fibroblasts ◽

Poor Prognostic Factor

Down-regulation of the small leucine-rich proteoglycan decorin in the stroma is considered a poor prognostic factor for breast cancer progression. Ionizing radiation, an established treatment for breast cancer, provokes the premature senescence of the adjacent to the tumor stromal fibroblasts. Here, we showed that senescent human breast stromal fibroblasts are characterized by the down-regulation of decorin at the mRNA and protein level, as well as by its decreased deposition in the pericellular extracellular matrix in vitro. Senescence-associated decorin down-regulation is a long-lasting process rather than an immediate response to γ-irradiation. Growth factors were demonstrated to participate in an autocrine manner in decorin down-regulation, with bFGF and VEGF being the critical mediators of the phenomenon. Autophagy inhibition by chloroquine reduced decorin mRNA levels, while autophagy activation using the mTOR inhibitor rapamycin enhanced decorin transcription. Interestingly, the secretome from a series of both untreated and irradiated human breast cancer cell lines with different molecular profiles inhibited decorin expression in young and senescent stromal fibroblasts, which was annulled by SU5402, a bFGF and VEGF inhibitor. The novel phenotypic trait of senescent human breast stromal fibroblasts revealed here is added to their already described cancer-promoting role via the formation of a tumor-permissive environment.

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Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/17588359211006680 ◽

2021 ◽

Vol 13 ◽

pp. 175883592110066

Author(s):

Eriko Katsuta ◽

Li Yan ◽

Mateusz Opyrchal ◽

Pawel Kalinski ◽

Kazuaki Takabe

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Patient Survival ◽

Cytotoxic T Lymphocyte ◽

Breast Cancer Patients ◽

Mutational Burden ◽

Cancer Immunity ◽

Anti Cancer ◽

Tumor Mutational Burden ◽

Patient Prognosis

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC.

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SEMA6D Expression and Patient Survival in Breast Invasive Carcinoma

International Journal of Breast Cancer ◽

10.1155/2015/539721 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 13

Author(s):

Dongquan Chen ◽

Yufeng Li ◽

Lizhong Wang ◽

Kai Jiao

Keyword(s):

Breast Cancer ◽

Expression Profile ◽

Heart Development ◽

Invasive Carcinoma ◽

Patient Survival ◽

The Cancer Genome Atlas ◽

Breast Cancer Patients ◽

Genomic Expression ◽

Cancer Genome Atlas ◽

Public Datasets

Breast cancer (BC) is the second most common cancer diagnosed in American women and is also the second leading cause of cancer death in women. Research has focused heavily on BC metastasis. Multiple signaling pathways have been implicated in regulating BC metastasis. Our knowledge of regulation of BC metastasis is, however, far from complete. Identification of new factors during metastasis is an essential step towards future therapy. Our labs have focused on Semaphorin 6D (SEMA6D), which was implicated in immune responses, heart development, and neurogenesis. It will be interesting to know SEMA6D-related genomic expression profile and its implications in clinical outcome. In this study, we examined the public datasets of breast invasive carcinoma from The Cancer Genome Atlas (TCGA). We analyzed the expression of SEMA6D along with its related genes, their functions, pathways, and potential as copredictors for BC patients’ survival. We found 6-gene expression profile that can be used as such predictors. Our study provides evidences for the first time that breast invasive carcinoma may contain a subtype based on SEMA6D expression. The expression of SEMA6D gene may play an important role in promoting patient survival, especially among triple negative breast cancer patients.

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