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Lab Invest. 2018 Jan;98(1):117-129. doi: 10.1038/labinvest.2017.106. Epub 2017 Oct 16.

Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β.

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Institute of Pathology, Hannover Medical School, Hannover, Germany.
Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany.
Department of Biomedicine, University of Basel, University Hospital Basel, Basel, Switzerland.
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
Division of Molecular Pathology, the Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany.
West German Study Group, Moenchengladbach, Germany.
Breast Center Niederrhein, Evangelic Bethesda Hospital, Moenchengladbach, Germany.
Breast Center, Department of Obstetrics and Gynecology, University of Munich, Munich, Germany.


Transcription factor AP-2β (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2β in breast cancer (BC). This study characterizes AP-2β expression in the mammary gland and in BC. AP-2β protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2β. The normal mammary gland epithelium showed scattered AP-2β-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2β expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2β-negative (P<0.001). In invasive BC cohorts, AP-2β-positivity was associated with the lobular BC subtype (P<0.001), loss of E-cadherin (P<0.001), a positive estrogen receptor (ER) status (P<0.001), low Ki67 (P<0.001), low/intermediate Oncotype DX recurrence scores (P<0.001), and prolonged event-free survival (P=0.003). BCs from GEM models were all AP-2β-negative. In human BC cell lines, AP-2β expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2β diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2β is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2β controls tumor cell proliferation in this slow-growing BC subtype.

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