A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women Under the Age of 50 Years.

BACKGROUND: Despite significant advances in breast imaging, the ability to detect breast cancer (BC) remains a challenge. To address the unmet needs of the current BC detection paradigm, 2 prospective clinical trials were conducted to develop a blood-based combinatorial proteomic biomarker assay (Videssa Breast) to accurately detect BC and reduce false positives (FPs) from suspicious imaging findings. PATIENTS AND METHODS: Provista-001 and Provista-002 (cohort one) enrolled Breast Imaging Reporting and Data System 3 or 4 women aged under 50 years. Serum was evaluated for 11 serum protein biomarkers and 33 tumor-associated autoantibodies. Individual biomarker expression, demographics, and clinical characteristics data from Provista-001 were combined to develop a logistic regression model to detect BC. The performance was tested using Provista-002 cohort one (validation set). RESULTS: The training model had a sensitivity and specificity of 92.3% and 85.3% (BC prevalence, 7.7%), respectively. In the validation set (BC prevalence, 2.9%), the sensitivity and specificity were 66.7% and 81.5%, respectively. The negative predictive value was high in both sets (99.3% and 98.8%, respectively). Videssa Breast performance in the combined training and validation set was 99.1% negative predictive value, 87.5% sensitivity, 83.8% specificity, and 25.2% positive predictive value (BC prevalence, 5.87%). Overall, imaging resulted in 341 participants receiving follow-up procedures to detect 30 cancers (90.6% FP rate). Videssa Breast would have recommended 111 participants for follow-up, a 67% reduction in FPs (P < .00001). CONCLUSIONS: Videssa Breast can effectively detect BC when used in conjunction with imaging and can substantially reduce unnecessary medical procedures, as well as provide assurance to women that they likely do not have BC.

Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2.

Bone morphogenetic proteins (BMPs) have an emerging role in human cancers. Here we demonstrate that the BMP-signaling pathway is intact and functional in human pancreatic cancer cells, with several BMP signaling components and transcriptional targets upregulated in human pancreatic cancer specimens compared with normal pancreatic tissue. Functionally, multiple BMP family members, including BMP-2, BMP-4 and BMP-7, induce an epithelial to mesenchymal transition (EMT) in the human pancreatic cancer cell line Panc-1, as demonstrated by morphological alterations and loss of E-cadherin expression. BMP-mediated EMT results in an increase in invasiveness of Panc-1 cells, in part through increased expression and activity of matrix metalloproteinase (MMP)-2, a known mediator of pancreatic cancer cell invasiveness. Accompanying EMT, BMP reduces expression of the transforming growth factor (TGF)-beta superfamily receptor, transforming growth factor-beta type III receptor (TbetaRIII), for which we have previously demonstrated loss of expression during pancreatic cancer progression. Maintaining TbetaRIII expression inhibits BMP-mediated invasion and suppresses Smad1 activation. Further, Smad1 is required for BMP-induced invasiveness and partially responsible for BMP-mediated increases in MMP-2 activity. These data suggest that BMP signaling, through Smad1 induction and upregulation of MMP-2, is an important mediator of pancreatic cancer invasiveness and a potential therapeutic target for treating this deadly disease.

Role of transforming growth factor-beta superfamily signaling pathways in human disease.

Transforming growth factor beta (TGF-beta) superfamily signaling pathways are ubiquitous and essential regulators of cellular processes including proliferation, differentiation, migration, and survival, as well as physiological processes, including embryonic development, angiogenesis, and wound healing. Alterations in these pathways, including either germ-line or somatic mutations or alterations in the expression of members of these signaling pathways often result in human disease. Appropriate regulation of these pathways is required at all levels, particularly at the ligand level, with either a deficiency or an excess of specific TGF-beta superfamily ligands resulting in human disease. TGF-beta superfamily ligands and members of these TGF-beta superfamily signaling pathways also have emerging roles as diagnostic, prognostic or predictive markers for human disease. Ongoing studies will enable targeting of TGF-beta superfamily signaling pathways for the chemoprevention and treatment of human disease.

Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression.

Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion.

The type III TGF-beta receptor suppresses breast cancer progression.

The TGF-beta signaling pathway has a complex role in regulating mammary carcinogenesis. Here we demonstrate that the type III TGF-beta receptor (TbetaRIII, or betaglycan), a ubiquitously expressed TGF-beta coreceptor, regulated breast cancer progression and metastasis. Most human breast cancers lost TbetaRIII expression, with loss of heterozygosity of the TGFBR3 gene locus correlating with decreased TbetaRIII expression. TbetaRIII expression decreased during breast cancer progression, and low TbetaRIII levels predicted decreased recurrence-free survival in breast cancer patients. Restoring TbetaRIII expression in breast cancer cells dramatically inhibited tumor invasiveness in vitro and tumor invasion, angiogenesis, and metastasis in vivo. TbetaRIII appeared to inhibit tumor invasion by undergoing ectodomain shedding and producing soluble TbetaRIII, which binds and sequesters TGF-beta to decrease TGF-beta signaling and reduce breast cancer cell invasion and tumor-induced angiogenesis. Our results indicate that loss of TbetaRIII through allelic imbalance is a frequent genetic event during human breast cancer development that increases metastatic potential.