Dataset Information

Nuclear CSPP1 expression defined subtypes of basal-like breast cancer.

ABSTRACT:

Background

The multi-exon CSPP1 gene, encoding for centrosome and microtubule-associated proteins involved in ciliogenesis and cell division, is a candidate oncogene in luminal breast cancer but expression of CSPP1 proteins remained unexplored.

Methods

CSPP1 gene and protein expression was examined in normal mammary tissue, human breast cancer cell lines, and primary breast cancer biopsies from two patient cohorts. Cell type and epitope-dependent subcellular-specific CSPP1 staining pattern in normal mammary gland epithelium and cancer biopsies were correlated to molecular and clinical parameters.

Results

A novel, nuclear localised CSPP1 isoform was exclusively detected in luminal epithelial cells, whereas cytoplasmic CSPP-L was generally expressed in normal mammary epithelium. Luminal cell-related nuclear CSPP1 expression was preserved in type-matched cell lines and carcinomas, and correlated to gene copy number and mRNA expression. In contrast, basal-like carcinomas displayed generally lower CSPP1 mRNA expression. Yet, a subgroup of basal-like breast carcinomas depicted nuclear CSPP1 expression, displayed luminal traits, and differed from nuclear CSPP1 devoid counterparts in expression of eight genes. Eight-gene signature defined groups of basal-like tumours from an independent cohort showed significant differences in survival.

Conclusions

Differential expression of a nuclear CSPP1 isoform identified biologically and clinically distinct subgroups of basal-like breast carcinoma.

SUBMITTER: Sternemalm J

PROVIDER: S-EPMC4102947 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Publications

Nuclear CSPP1 expression defined subtypes of basal-like breast cancer.

Sternemalm J J Russnes H G HG Zhao X X Risberg B B Nord S S Caldas C C Børresen-Dale A L AL Stokke T T Patzke S S

British journal of cancer 20140605 2

<h4>Background</h4>The multi-exon CSPP1 gene, encoding for centrosome and microtubule-associated proteins involved in ciliogenesis and cell division, is a candidate oncogene in luminal breast cancer but expression of CSPP1 proteins remained unexplored.<h4>Methods</h4>CSPP1 gene and protein expression was examined in normal mammary tissue, human breast cancer cell lines, and primary breast cancer biopsies from two patient cohorts. Cell type and epitope-dependent subcellular-specific CSPP1 stainin ...[more]

PMID: 24901235

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Project description:Rationale: Basal-like breast cancer (BLBC) is associated with high grade, distant metastasis, and poor prognosis; however, the mechanism underlying aggressiveness of BLBC is still unclear. Emerging evidence has suggested that phospholipid scramblase 1 (PLSCR1) is involved in tumor progression. Here, we aimed to study the possible involvement and molecular mechanisms of PLSCR1 contributing to the aggressive behavior of BLBC. Methods: The potential functions of PLSCR1 in breast cancer cells were assessed by Western blotting, colony formation, migration and invasion, Cell Counting Kit-8 assay, mammosphere formation and flow cytometry. The relationship between nuclear translocation of PLSCR1 and transactivation of STAT1 was examined by immunostaining, co-IP, ChIP, and quantitative reverse transcription PCR. The effect of PLSCR1 expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model. Results: Compared to other subtypes, PLSCR1 was considerably increased in BLBC. Phosphorylation of PLSCR1 at Tyr 69/74 contributed to the nuclear translocation of this protein. PLSCR1 was enriched in the promoter region of STAT1 and enhanced STAT3 binding to the STAT1 promoter, resulting in transactivation of STAT1; STAT1 then enhanced cancer stem cell (CSC)-like properties that promoted BLBC progression. The knockdown of PLSCR1 led to significant inhibitory effects on proliferation, migration, invasion, tumor growth and lung metastasis of BLBC cells. Clinically, high PLSCR1 expression was strongly correlated with large tumor size, high grade, metastasis, chemotherapy resistance, and poor survival, indicating poor prognosis in breast cancer patients. Conclusions: Our data show that overexpression and nuclear translocation of PLSCR1 provide tumorigenic and metastatic advantages by activating STAT1 signaling in BLBC. This study not only reveals a critical mechanism of how PLSCR1 contributes to BLBC progression, but also suggests potential prognostic indicators and therapeutic targets for this challenging disease.

Project description:BackgroundSubtypes defined by hormonal receptor (HR) and HER2 status have not been well studied in inflammatory breast cancer (IBC). We characterized clinical parameters and long-term outcomes, and compared pathological complete response (pCR) rates by HR/HER2 subtype in a large IBC patient population. We also compared disease-free survival (DFS) and overall survival (OS) between IBC patients who received targeted therapies (anti-hormonal, anti-HER2) and those who did not.Patients and methodsWe retrospectively reviewed the records of patients diagnosed with IBC and treated at MD Anderson Cancer Center from January 1989 to January 2011. Of those, 527 patients had received neoadjuvant chemotherapy and had available information on estrogen receptor (ER), progesterone receptor (PR), and HER2 status. HR status was considered positive if either ER or PR status was positive. Using the Kaplan-Meier method, we estimated median DFS and OS durations from the time of definitive surgery. Using the Cox proportional hazards regression model, we determined the effect of prognostic factors on DFS and OS. Results were compared by subtype.ResultsThe overall pCR rate in stage III IBC was 15.2%, with the HR-positive/HER2-negative subtype showing the lowest rate (7.5%) and the HR-negative/HER2-positive subtype, the highest (30.6%). The HR-negative, HER2-negative subtype (triple-negative breast cancer, TNBC) had the worst survival rate. HR-positive disease, irrespective of HER2 status, had poor prognosis that did not differ from that of the HR-negative/HER2-positive subtype with regard to OS or DFS. Achieving pCR, no evidence of vascular invasion, non-TNBC, adjuvant hormonal therapy, and radiotherapy were associated with longer DFS and OS.ConclusionsHormone receptor and HER2 molecular subtypes had limited predictive and prognostic power in our IBC population. All molecular subtypes of IBC had a poor prognosis. HR-positive status did not necessarily confer a good prognosis. For all IBC subtypes, novel, specific treatment strategies are needed in the neoadjuvant and adjuvant settings.

Dataset Information

Nuclear CSPP1 expression defined subtypes of basal-like breast cancer.

Background

Methods

Results

Conclusions

Publications

Nuclear CSPP1 expression defined subtypes of basal-like breast cancer.

Similar Datasets

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