FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis

Abstract

SUMMARYFOXA1, estrogen receptor a (ERa) and GATA3 independently predict favorable outcome in breast cancer patients, and their expression correlates with a differentiated, luminal tumor subtype. As transcription factors, each functions in the morphogenesis of various organs, with ERa and GATA3 being established regulators of mammary gland development. Interdependency between these three factors in breast cancer and normal mammary development has been suggested, but the specific role for FOXA1 is not known. Herein, we report that Foxa1 deficiency causes a defect in hormone-induced mammary ductal invasion associated with a loss of terminal end bud formation and ERa expression. By contrast, Foxa1 null glands maintain GATA3 expression. Unlike ERa and GATA3 deficiency, Foxa1 null glands form milk-producing alveoli, indicating that the defect is restricted to expansion of the ductal epithelium, further emphasizing the novel role for FOXA1 in mammary morphogenesis. Using breast cancer cell lines, we also demonstrate that FOXA1 regulates ERa expression, but not GATA3. These data reveal that FOXA1 is necessary for hormonal responsiveness in the developing mammary gland and ERa-positive breast cancers, at least in part, through its control of ERa expression.

Histone Demethylase Jumonji AT-rich Interactive Domain 1B (JARID1B) Controls Mammary Gland Development by Regulating Key Developmental and Lineage Specification Genes

“…In fact, FOXA1 was shown to be indispensable in long range chromatin remodeling and ER␣ access of target genes, such as cyclin D1 (37). Furthermore, FOXA1 function in the mammary gland is critical for ductal invasion during puberty but not essential for alveologenesis in pregnancy and lactation (28), which is remarkably similar to the phenotype observed in our Jarid1b Ϫ/Ϫ animals. The persistent down-regulation of FOXA1 in the Jarid1b Ϫ/Ϫ mammary epithelium uncovered by our study also illustrates that a transcription factor with unique chromatin remodeling functions can be directly modulated by another epigenetic regulator.…”

“…In particular, FOXA1 acts upstream of ER␣ in TEB formation and ductal invasion and plays an indispensable role in ER␣-dependent transcription (27,28). RT-qPCR experiments showed that expression of other previously identified mammary gland morphogenesis regulators, such as Elf5, Erbb2, Erbb3, Pgr, Stat5a, Tgfb1, and Esr1, were also significantly reduced upon JARID1B loss (Fig.…”

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

“…4A ). shRNA-mediated knockdown of RAI2 protein expression caused downregulation of ERα protein expression in all three of the tested cell lines and a concomitant downregulation of the expression of GATA3, FOXA1, and GRHL2 proteins, which are known to be key regulators of breast epithelial differentiation (14)(15)(16). Furthermore, Western blot analysis further revealed decreased protein expression of the transcriptional coregulators carboxyl-terminal binding proteins (CtBP) 1 and 2 ( Furthermore, loss of RAI2 protein expression led to an apparent alteration in cellular morphology.…”

FOXA1 Is Essential for Aryl Hydrocarbon Receptor–Dependent Regulation of Cyclin G2

“…Although the RNAi-mediated knockdown of FOXA1 was reported to not affect ERa protein levels (35), we and others report that knockdown of FOXA1 has been shown to decrease ERa mRNA expression and protein levels (34). The reason for the discrepancies between the studies is unclear, but we observe that RNAi-mediated knockdown of FOXA1 reduces ERa protein levels in 2 different cell lines (T-47D, Fig.…”

“…FOXA1 is an important modulator of ERa and androgen receptor transactivation in breast and prostate cancer cells, respectively (25,26,(34)(35)(36). Because FKH sites were found to be important in the TCDD-mediated regulation of the CCNG2 luciferase reporter plasmid, we hypothesized that FOXA1 may have a similar role with AHR-chromatin interactions at CCNG2.…”