tough reading--how estrogen stimulates breast cancer cell growth details discovered
 

with the human genome project information more is being discovered. Estrogen does not work alone but requires FoxA1 to bind to the chromosome and transcribe the right genes

As more is discovered, better , more specific drugs than AIs may be discovered.

Battling breast cancer [Eureka News Service]
Dr. Myles Brown and colleagues (Dana Farber Cancer Institute) lend new insight into the transcriptional network that drives breast cancer cell proliferation in response to estrogen exposure. The majority of human breast cancers express estrogen receptor alpha (ERalpha), and grow and divide in response to estrogen. The authors have discovered that ERalpha binds to a novel enhancer in the cyclin D1 gene (CCND1) to promote estrogen-responsive cell proliferation. The researchers also delineate a number of other associated transcription factors that cooperate to regulate CCND1 expression and cell proliferation in breast cancer cells. Dr. Brown is hopeful that "the basic understanding of how estrogen promotes breast cancer growth revealed by our work will lead to the development of improved therapies that impact the lives of patients with the disease."


ABSTRACT: A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer [Genes & Development; Subscribe; Sample]
Estrogen stimulates the proliferation of the most common type of human breast cancer that expresses estrogen receptor ? (ER?) through the activation of the cyclin D1 (CCND1) oncogene. However, our knowledge of ER? transcriptional mechanisms remains limited. Hence, it is still elusive why ER? ectopically expressed in ER-negative breast cancer cells (BCC) is functional on ectopic reporter constructs but lacks activity on many endogenous target genes, including CCND1. Here, we show that estradiol (E2) stimulation of CCND1 expression in BCC depends on a novel cell-type-specific enhancer downstream from the CCND1 coding region, which is the primary ER? recruitment site in estrogen-responsive cells. The pioneer factor FoxA1 is specifically required for the active chromatin state of this enhancer and as such is crucial for both CCND1 expression and subsequent cell cycle progression. Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription. Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ER? collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC.