TFAP2C Controls Hormone Response in Breast Cancer Cells through Multiple Pathways of Estrogen Signaling

Abstract

Breast cancers expressing estrogen receptor-A (ERA) are associated with a favorable biology and are more likely to respond to hormonal therapy. In addition to ERA, other pathways of estrogen response have been identified including ERB and GPR30, a membrane receptor for estrogen, and the key mechanisms regulating expression of ERs and hormone response remain controversial. Herein, we show that TFAP2C is the key regulator of hormone responsiveness in breast carcinoma cells through the control of multiple pathways of estrogen signaling. TFAP2C regulates the expression of ERA directly by binding to the ERA promoter and indirectly via regulation of FoxM1. In so doing, TFAP2C controls the expression of ERA target genes, including pS2, MYB, and RERG. Furthermore, TFAP2C controlled the expression of GPR30. In distinct contrast, TFAP2A, a related factor expressed in breast cancer, was not involved in estrogen-mediated pathways but regulated expression of genes controlling cell cycle arrest and apoptosis including p21 CIP1 and IGFBP-3.Knockdown of TFAP2C abrogated the mitogenic response to estrogen exposure and decreased hormone-responsive tumor growth of breast cancer xenografts. We conclude that TFAP2C is a central control gene of hormone response and is a novel therapeutic target in the design of new drug treatments for breast cancer.

Differential Regulation of Estrogen Receptor α Expression in Breast Cancer Cells by Metastasis-Associated Protein 1

“…In an earlier study, it was reported that TFAP2C could be purified from a protein complex bound to a region of the ESR1 promoter including the ERpro315 (þ146 to þ461) region (42). Subsequently, TFAP2C was shown to upregulate ESR1 expression in breast cancer cells by alteration of chromatin structure (32,33). Here, we demonstrated that MTA1 binds to TFAP2C and is required for TFAP2C-induced ESR1 activation (Figs.…”

“…As the role of androgen receptor in breast cancer development and treatment has attracted attention, understanding of the function of IFI16 in hormone resistance and transcriptional regulation of hormone receptors may contribute to development of a novel strategy to treat breast cancer (41). TFAP2C, the expression of which decreases during hormone therapy, is considered an independent predictor of poor survival in patients with breast cancer (33). In an earlier study, it was reported that TFAP2C could be purified from a protein complex bound to a region of the ESR1 promoter including the ERpro315 (þ146 to þ461) region (42).…”

TFAP2E–DKK4and Chemoresistance in Colorectal Cancer

“…17 TFAP2B seems to play a role in diabetes. 18 TFAP2C acts as a tumor suppressor in breast cancer 19 and may predict tamoxifen resistance through its relation to human epidermal growth factor receptor type 2 (HER2). 20 TFAP2D and TFAP2E have also been shown to be hypermethylated in prostate and colorectal cancer.…”

Amplitude modulation of androgen signaling by c-MYC

“…For example, AP2g, an estrogen-induced ER target gene, serves as another pioneer factor for ER function (Tan et al 2011) and also regulates the transcription of the ER gene ESR1 itself (Woodfield et al 2007). Thus, the function of ER is co-opted to promote the growth of ER + breast cancers.…”