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Cyclin E Overexpression Obstructs Infiltrative Behavior in Breast Cancer: A Novel Role Reflected in the Growth Pattern of Medullary Breast Cancers

Divisions of ¹ Pathology and ² Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden

Requests for reprints: Göran Landberg, Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, 20502 Malmö, Sweden. Phone: 46-4033-1953; Fax: 46-4033-7063; E-mail: goran.landberg{at}pat.mas.lu.se.

Cell cycle deregulation is a prerequisite in tumor development and overexpression of cyclin E, a major G₁-S regulator, is often observed in breast cancer and is further linked to poor prognosis. By overexpressing cyclin E in a retinoblastoma-inactivated breast cancer cell line, we induced significant alterations in the expression of genes associated with proliferation and cell adhesion. Rearrangements of the actin cytoskeleton in addition to increased adhesive properties, decreased motility, and invasive potential in functional assays, indicated an overall abrogated mobility. Consistent in vivo findings were obtained upon investigation of 985 primary breast cancers, where cyclin E–high tumors predominantly (67%) displayed a low infiltrative, pushing growth pattern. Furthermore, medullary breast cancers, a subtype defined by its pushing, delimited growth, exhibited a remarkable frequency of cyclin E deregulation (87%) compared with other histologic subtypes (5-20%). Taken together, our results suggest the novel role of cyclin E in modeling infiltrative behavior. The consequences of cyclin E overexpression in breast cancer seems to be multiple, including effects on proliferation as well as growth patterns, a scenario that is indeed observed in the archetype of cyclin E–overexpressing medullary breast cancers.

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