TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis

• Published in: Oncogene Vol. 34; no. 4; pp. 436 - 444
• Main Authors: Cyr, A R, Kulak, M V, Park, J M, Bogachek, M V, Spanheimer, P M, Woodfield, G W, White-Baer, L S, O'Malley, Y Q, Sugg, S L, Olivier, A K, Zhang, W, Domann, F E, Weigel, R J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-01-2015; Nature Publishing Group
• Subjects: 631/136; 631/136/1660/2176; 631/67/1347; Animals; Apoptosis; Breast - growth & development; Breast cancer; Breast carcinoma; Breast Neoplasms - etiology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinogenesis; CD24 Antigen - analysis; Cell Biology; Cell differentiation; Cell Line, Tumor; Development and progression; Epithelial-Mesenchymal Transition; Epithelium; Estrogen receptors; Female; Gene expression; Genetic aspects; Genotype & phenotype; Health aspects; Human Genetics; Humans; Hyaluronan Receptors - analysis; Internal Medicine; Mammary gland; Medicine; Medicine & Public Health; Mesenchyme; Mice; Mice, Knockout; Molecular biology; Neoplastic Stem Cells - chemistry; Oncology; original-article; Phenotype; Phenotypes; Physiological aspects; Protein 2C; Risk factors; Therapeutic applications; Transcription Factor AP-2 - analysis; Transcription Factor AP-2 - physiology; Transcription factors; United States; breast cancer; TFAP2C; mammary development; luminal; EMT; gene expression
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.569

Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor-alpha (ERα)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating
ESR1/ERα
and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial–mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal-associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of
TFAP2C
,
Tcfap2c
, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24
hi
/CD49f
mid
luminal cell population and concomitant gain of the CD24
mid
/CD49f
hi
basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer.