title: Early dysregulation of cell adhesion and extracellular matrix pathways in breast cancer progression.
abstract: Proliferative breast lesions, such as simple ductal hyperplasia (SH) and atypical ductal hyperplasia (ADH), are candidate precursors to ductal carcinoma in situ (DCIS) and invasive cancer. To better understand the relationship of breast lesions to more advanced disease, we used microdissection and DNA microarrays to profile the gene expression of patient-matched histologically normal (HN), ADH, and DCIS from 12 patients with estrogen receptor positive sporadic breast cancer. SH were profiled from a subset of cases. We found 837 differentially expressed genes between DCIS-HN and 447 between ADH-HN, with >90% of the ADH-HN genes also present among the DCIS-HN genes. Only 61 genes were identified between ADH-DCIS. Expression differences were reproduced in an independent cohort of patient-matched lesions by quantitative real-time PCR. Many breast cancer-related genes and pathways were dysregulated in ADH and maintained in DCIS. Particularly, cell adhesion and extracellular matrix interactions were overrepresented. Focal adhesion was the top pathway in each gene set. We conclude that ADH and DCIS share highly similar gene expression and are distinct from HN. In contrast, SH appear more similar to HN. These data provide genetic evidence that ADH (but not SH) are often precursors to cancer and suggest cancer-related genetic changes, particularly adhesion and extracellular matrix pathways, are dysregulated before invasion and even before malignancy is apparent. These findings could lead to novel risk stratification, prevention, and treatment approaches.
authors.affiliation: Boston University Medical Center, 650 Albany Street, Boston, MA 02118, USA.
authors.forename: Lyndsey A
authors.initials: LA
authors.lastname: Emery
authors.forename: Anusri
authors.initials: A
authors.lastname: Tripathi
authors.forename: Chialin
authors.initials: C
authors.lastname: King
authors.forename: Maureen
authors.initials: M
authors.lastname: Kavanah
authors.forename: Jane
authors.initials: J
authors.lastname: Mendez
authors.forename: Michael D
authors.initials: MD
authors.lastname: Stone
authors.forename: Antonio
authors.initials: A
authors.lastname: de las Morenas
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Carol L
authors.initials: CL
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001940:Breast / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics*; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006965:Hyperplasia; D008875:Middle Aged; D015398:Signal Transduction / Q000235:genetics
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