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Raap, Mieke; Gronewold, Malte; Christgen, Henriette; Glage, Silke; Bentires-Alj, Mohammad; Koren, Shany; Derksen, Patrick W.; Bölens, Mirjam; Jonkers, Jos; Lehmann, Ulrich; Feuerhake, Friedrich; Kühnle, Elna; Gluz, Oleg; Kates, Ronald; Nitz, Ulrike; Harbeck, Nadia; Kreipe, Hans H.; Christgen, Matthias (2018): Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2 beta. In: Laboratory Investigation, Vol. 98, No. 1: pp. 117-129
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Abstract

Transcription factor AP-2 beta (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2 beta in breast cancer (BC). This study characterizes AP-2 beta expression in the mammary gland and in BC. AP-2 beta 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-2 beta. The normal mammary gland epithelium showed scattered AP-2 beta-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-2 beta expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2 beta-negative (P < 0.001). In invasive BC cohorts, AP-2 beta-positivity was associated with the lobular BC subtype (P < 0.001), loss of E-cadherin (Po0.001), a positive estrogen receptor (ER) status (Po0.001), low Ki67 (P < 0.001), low/intermediate Oncotype DX recurrence scores (Po0.001), and prolonged event-free survival (P = 0.003). BCs from GEM models were all AP-2 beta-negative. In human BC cell lines, AP-2 beta expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2 beta diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2 beta 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-2 beta controls tumor cell proliferation in this slow-growing BC subtype.