Abstract
Simple SummaryFactors such as estrogen, progesterone, and androgen receptors, also known as nuclear receptors, are abundantly expressed in the majority of breast cancers where they serve as critical regulators of tumor growth and metastatic disease. The ability of these receptors to regulate breast cancer cell functions depends on their interactions with DNA to control the activity of a large number of genes. FOXA1 is a protein that is highly expressed in a majority of breast cancers and its binding to DNA helps define which genes are regulated by nuclear receptors. This review discusses the current literature on how FOXA1 controls gene activity, cell biology, and the response of breast cancers to hormone therapies. It also offers areas of future study to identify roles of FOXA1 in controlling breast cancers that is independent of its regulation of nuclear receptors.The pioneering function of FOXA1 establishes estrogen-responsive transcriptomes in luminal breast cancer. Dysregulated FOXA1 chromatin occupancy through focal amplification, mutation, or cofactor recruitment modulates estrogen receptor (ER) transcriptional programs and drives endocrine-resistant disease. However, ER is not the sole nuclear receptor (NR) expressed in breast cancers, nor is it the only NR for which FOXA1 serves as a licensing factor. Receptors for androgens, glucocorticoids, and progesterone are also found in the majority of breast cancers, and their functions are also impacted by FOXA1. These NRs interface with ER transcriptional programs and, depending on their activation level, can reprogram FOXA1-ER cistromes. Thus, NR interplay contributes to endocrine therapy response and resistance and may provide a vulnerability for future therapeutic benefit in patients. Herein, we review what is known regarding FOXA1 regulation of NR function in breast cancer in the context of cell identity, endocrine resistance, and NR crosstalk in breast cancer progression and treatment.
Highlights
The pioneering functions of FOXA1 and nuclear receptor (NR) transcriptional programs are tightly coupled in breast cancer
Among the ~40 NR family members expressed in breast cancer [2], the receptors for estrogens, androgens, glucocorticoids, and retinoic acid receptor are dependent upon FOXA1 for chromatin access and transcriptional regulation, with the estrogen receptor-α isoform (ER) being the most clinically relevant
Therapeutic targeting of ER signaling for breast cancer management using selective ER modulators (SERMs; i.e., tamoxifen), aromatase inhibitors, or selective ER degraders (SERDS; i.e., fulvestrant) provides long-term benefit for the majority of patients with early-stage disease and extends the lives of many patients with advanced lesions
Summary
The pioneering functions of FOXA1 and nuclear receptor (NR) transcriptional programs are tightly coupled in breast cancer. Among the ~40 NR family members expressed in breast cancer [2], the receptors for estrogens, androgens, glucocorticoids, and retinoic acid receptor are dependent upon FOXA1 for chromatin access and transcriptional regulation, with the estrogen receptor-α isoform (ER) being the most clinically relevant. A second isoform of estrogen receptor is expressed in breast cancer (ER-β/ESR2); the relative contributions of ER-β to this disease are less well understood (reviewed in [3]). PR expression is a biomarker of active ER and is associated with increased breast cancer patient survival. We provide an update on the role of FOXA1 in controlling NR function in breast cancer and identify areas requiring additional focus to delineate the full spectrum of FOXA1 functions in this disease
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