Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

Alajati, Abdullah; Guccini, Ilaria; Pinton, Sandra; García-Escudero, Ramón; Bernasocchi, Tiziano; Sarti, Manuela; Montani, Erica; Rinaldi, Andrea; Montemurro, Filippo; Catapano, Carlo V.; Bertoni, Francesco; Alimonti, Andrea

doi:10.1016/j.celrep.2015.03.044

Cited by 52 publications

(57 citation statements)

References 42 publications

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“…S6A), whereas CDCP1 knockdown did not change proliferation (SI Appendix, Fig. S6B), consistent with previous reports for cell types other than TNBC (44,45). Because CDCP1 is known to regulate multiple pathways in addition to ACSL (1,5,13,14,46,47), it is likely that these override the effect of the CDCP1/ACSL axis on cell proliferation.…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Casupporting

confidence: 78%

“…Homozygous germline CDCP1 knockout in a MMTVPyMT spontaneous mouse model lead to increased tumor growth rate (68). However, in a BT474-based mouse model, CDCP1 overexpression led to increased tumor growth (44). Furthermore, high coexpression of CDCP1 and HER2 was correlated with decreased patient survival (44).…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

“…This observation also implies that the average CDCP1 expression and activity should be higher at metastatic sites than in corresponding primary tumors. Accordingly, Alajati et al (44) reported that CDCP1 expression is higher in HER2 + patient breast cancer metastases than the primary tumors. It is important to note that although our data support the mechanism where low LD abundance stems from CDCP1 overexpression and lipid FAO, thus depleting LDs, the dynamics of lipid metabolism in TNBC tumor tissue is largely unknown.…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

“…However, in a BT474-based mouse model, CDCP1 overexpression led to increased tumor growth (44). Furthermore, high coexpression of CDCP1 and HER2 was correlated with decreased patient survival (44). It will be important to investigate the regulation of lipid metabolism by CDCP1 across breast cancer subtypes.…”

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

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CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

149

102

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Triple-negative breast cancer (TNBC) is notoriously aggressive with high metastatic potential, which has recently been linked to high rates of fatty acid oxidation (FAO). Here we report the mechanism of lipid metabolism dysregulation in TNBC through the prometastatic protein, CUB-domain containing protein 1 (CDCP1). We show that a "low-lipid" phenotype is characteristic of breast cancer cells compared with normal breast epithelial cells and negatively correlates with invasiveness in 3D culture. Using coherent anti-Stokes Raman scattering and two-photon excited fluorescence microscopy, we show that CDCP1 depletes lipids from cytoplasmic lipid droplets (LDs) through reduced acyl-CoA production and increased lipid utilization in the mitochondria through FAO, fueling oxidative phosphorylation. These findings are supported by CDCP1's interaction with and inhibition of acyl CoA-synthetase ligase (ACSL) activity. Importantly, CDCP1 knockdown increases LD abundance and reduces TNBC 2D migration in vitro, which can be partially rescued by the ACSL inhibitor, Triacsin C. Furthermore, CDCP1 knockdown reduced 3D invasion, which can be rescued by ACSL3 co-knockdown. In vivo, inhibiting CDCP1 activity with an engineered blocking fragment (extracellular portion of cleaved CDCP1) lead to increased LD abundance in primary tumors, decreased metastasis, and increased ACSL activity in two animal models of TNBC. Finally, TNBC lung metastases have lower LD abundance than their corresponding primary tumors, indicating that LD abundance in primary tumor might serve as a prognostic marker for metastatic potential. Our studies have important implications for the development of TNBC therapeutics to specifically block CDCP1-driven FAO and oxidative phosphorylation, which contribute to TNBC migration and metastasis.he transmembrane glycoprotein, CUB-domain containing protein 1 (CDCP1), is a driver of migration and invasion in multiple forms of carcinoma, including renal (1, 2), ovarian (3, 4), prostate (5), pancreatic (6, 7), colon (8-12), and triple-negative breast (TNBC) (13, 14) carcinomas, among others. Furthermore, CDCP1's role in tumor metastasis was confirmed in vivo in lung (15, 16), ovarian (17), prostate (5), and colon (9) cancers. Although CDCP1's role in TNBC metastasis has not been established to date, high CDCP1 expression has been validated as a prognostic marker of poor survival in TNBC when combined with positive node status (18).Our understanding of CDCP1's upstream regulators, its mechanism of activation, and downstream signaling continues to expand (recently reviewed in ref. 19). Studies by others (5) and our group (14) have demonstrated that CDCP1 cleavage is necessary for its activation, and recently, we have further shown that cleavage stimulates CDCP1 homodimerization (14). Homodimeric CDCP1 stimulates phosphorylation of protein kinase C δ (PKCδ) by Src kinase, leading to migration and invasion of TNBC cells in vitro (14). Adding to our knowledge of CDCP1's downstream signaling, we report that CDCP1 regulates lipid m...

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Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Casupporting

confidence: 78%

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

Section: Low-lipid Content Favors Promigratory Phenotype Of Breast Camentioning

confidence: 99%

See 2 more Smart Citations

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Wright

Hou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

149

102

View full text Add to dashboard Cite

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“…It is expressed by epithelial cells of most organs [1][2][3] and its over-expression is associated with poor survival of patients with renal cell carcinoma [4,5], colorectal [6], lung [7,8], pancreatic [9], and breast cancer [10], and clear cell ovarian carcinoma [11]. CDCP1 modulates adhesion and promotes motility of cells in vitro [2,9,[12][13][14], mediates metastasis in in vivo models [11,12,[14][15][16][17], and also contributes to in vitro and in vivo resistance of cancer to chemotherapy [11,17] and targeted agents [10,18,19].…”

Section: Introductionmentioning

confidence: 99%

Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens

Chen

Harrington

Lau

et al. 2017

Journal of Pharmaceutical and Biomedical Analysis

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Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens, Journal of Pharmaceutical and Biomedical Analysis http://dx.doi.org/10. 1016/j.jpba.2017.02.047 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HIGHLIGHTS 1. First report of an enzyme-linked immunosorbent assay (ELISA) to detect fragments of the protein CDCP1 in human serum 2. The ELISA has a wide working range of 0.68 to 26.5 ng/ml, and a low limit of detection of 0.25 ng/ml 3. The ELISA has high intra-assay (repeatability) and high inter-assay (reproducibility) precision with all coefficients of variation ≤ 7% 4. The ELISA displays high accuracy detecting ShE-CDCP1 levels at ≥ 94.8% of actual concentration 5. Because CDCP1 has potential as a biomarker for colorectal, prostate, breast, kidney and ovarian cancer, the findings will be relevant to investigators interested in clinical applications as well as those interested in the functions of CDCP1.ABSTRACT CUB domain containing protein 1 (CDCP1) is a transmembrane protein involved in progression of several cancers. When located on the plasma membrane, full-length 135 kDa CDCP1 can undergo proteolysis mediated by serine proteases that cleave after two adjacent amino acids (arginine 368 and lysine 369). This releases from the cell surface two 65 kDa fragments, collectively termed ShE-CDCP1, that differ by one carboxyl terminal residue. To evaluate the function of CDCP1 and its potential utility as a cancer biomarker, in this study we developed an enzyme-linked immunosorbent assay (ELISA) to reliably and easily measure the concentration of ShE-CDCP1 in biological samples. Using a reference standard we demonstrate that the developed ELISA has a working range of 0.68 to 26.5 ng/ml, and the limit of detection is 0.25 ng/ml. It displays high intra-assay (repeatability) and high inter-assay (reproducibility) precision 2 with all coefficients of variation ≤ 7%. The ELISA also displays high accuracy detecting ShE-CDCP1 levels at ≥ 94.8% of actual concentration using quality control samples. We employed the ELISA to measure the concentration of ShE-CDCP1 in human serum samples with our results suggesting that levels are significantly higher in serum of colorectal cancer patients compared with serum from individuals with benign conditions (p < 0.05). Our data also suggest that colorectal cancer patients with stage II-IV disease have at least 50% higher serum levels of ShE-CDCP1 compared with stage I cases (p < 0.05). We conclude that the developed ELISA is a suitable method to quantify ShE-CDCP1 concentration in ...

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Fusion‐associatedcarcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

Loo

Yates

Yang

et al. 2022

Genes Chromosomes & Cancer

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Recurrent gene fusions comprise a class of viable genetic targets in solid tumors that have culminated several recent breakthrough cancer therapies. Their role in breast cancer, however, remains largely underappreciated due to the complexity of genomic rearrangements in breast malignancy. Just recently, we and others have identified several recurrent gene fusions in breast cancer with important clinical and biological implications. Examples of the most significant recurrent gene fusions to date include (1) ESR1::CCDC170 gene fusions in luminal B and endocrine‐resistant breast cancer that exert oncogenic function via modulating the HER2/HER3/SRC Proto‐Oncogene (SRC) complex, (2) ESR1 exon 6 fusions in metastatic disease that drive estrogen‐independent estrogen‐receptor transcriptional activity, (3) BCL2L14::ETV6 fusions in a more aggressive form of the triple‐negative subtype that prime epithelial–mesenchymal transition and endow paclitaxel resistance, (4) the ETV6::NTRK3 fusion in secretory breast carcinoma that constitutively activates NTRK3 kinase, (5) the oncogenic MYB‐NFIB fusion as a genetic driver underpinning adenoid cystic carcinomas of the breast that activates MYB Proto‐Oncogene (MYB) pathway, and (6) the NOTCH/microtubule‐associated serine–threonine (MAST) kinase gene fusions that activate NOTCH and MAST signaling. Importantly, these fusions are enriched in more aggressive and lethal breast cancer presentations and appear to confer therapeutic resistance. Thus, these gene fusions could be utilized as genetic biomarkers to identify patients who require more intensive treatment and surveillance. In addition, kinase fusions are currently being evaluated in breast cancer clinical trials and ongoing mechanistic investigation is exposing therapeutic vulnerabilities in patients with fusion‐positive disease.

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Interaction of CDCP1 with HER2 Enhances HER2-Driven Tumorigenesis and Promotes Trastuzumab Resistance in Breast Cancer

Cited by 52 publications

References 42 publications

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

Development of an enzyme-linked immunosorbent assay for detection of CDCP1 shed from the cell surface and present in colorectal cancer serum specimens

Fusion‐associatedcarcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

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