title: Harnessing 3D models of mammary epithelial morphogenesis: An off the beaten path approach to identify candidate biomarkers of early stage breast cancer.
abstract: Regardless of the etiological factor, an aberrant morphology is the common hallmark of ductal carcinoma in situ (DCIS), which is a highly heterogeneous disease. To test if critical core morphogenetic mechanisms are compromised by different mutations, we performed proteomics analysis of five mammary epithelial HME1 mutant lines that develop a DCIS-like morphology in three dimensional (3D) culture. Here we show first, that all HME1 mutant lines share a common protein signature highlighting an inverse deregulation of two annexins, ANXA2 and ANXA8. Either ANXA2 downregulation or ANXA8 upregulation in the HME1 cell context are per se sufficient to confer a 3D DCIS-like morphology. Seemingly, different mutations impinged on a common mechanism that differentially regulates the two annexins. Second, we show that ANXA8 expression is significantly higher in DCIS tissue samples versus normal breast tissue and atypical ductal hyperplasia (ADH). Apparently, ANXA8 expression is significantly more upregulated in ER-negative versus ER-positive cases, and significantly correlates with tumor stage, grade and positive lymph node. Based on our study, 3D mammary morphogenesis models can be an alternate/complementary strategy for unraveling new DCIS mechanisms and biomarkers.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossetti
authors.affiliation: Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Reiners
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Corlazzoli
authors.affiliation: Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: nicoletta.sacchi@roswellpark.org.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
mesh_terms: D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D009024:Morphogenesis; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D040901:Proteomics / Q000379:methods; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen
keywords: 3D mammary epithelial morphogenesis; Annexins; Biomarkers; Breast cancer; Ductal carcinoma in situ (DCIS)