Year: 2019
Type: article
Abstract: Breast cancer is the most frequently diagnosed malignancy in women.The vast majority (>70%) of breast cancer patients are diagnosed with the estrogen receptor-positive subtype.These cancers express the transcription factor estrogen receptor α (ER) and depend on its activation and subsequent regulation of estrogen-responsive genes for survival and proliferation.Patients diagnosed with ER-positive breast cancer are typically given endocrine therapies that target the activity of the ER.Although endocrine therapies are initially effective, patients invariably develop resistance to currently available treatments, underscoring the need to better characterize the mechanism by which ER-target genes drive proliferation in order to develop new and innovative therapies.One gene target of ER, growth regulation by estrogen in breast cancer 1 (GREB1), is associated with proliferation of ER-positive breast cancer cells.The GREB1 gene encodes three distinct protein isoforms: GREB1a, GREB1b, and GREB1c.Unfortunately, few studies have investigated the mechanism by which GREB1 regulates proliferation and no studies have investigated the isoform specific molecular functions of GREB1.Here, I investigate the role of the GREB1 isoforms in modulation of ER activity and proliferation.I show that all three isoforms interact with ER through their homologous amino terminus.Analysis of iii isoform-specific regulation of ER activity reveals that none of the GREB1 isoforms are potent regulators of ER activity.Interestingly, exogenous expression of GREB1a, but not GREB1b, was associated with increased expression of some ER-target genes and this function was independent of ER activity.While these data demonstrate diverging roles for GREB1a and GREB1b in modulation of gene expression, exogenous expression of either GREB1a or GREB1b resulted in similar patterns of growth repression in breast cancer cell lines, independent of ER expression.Analysis of GREB1 isoform expression in cell lines and patient samples reveals that while GREB1a is the predominant isoform, there appears to be an increase in the expression of both GREB1b and GREB1c in malignant patient samples compared to normal patient samples.Taken together, these data suggest that GREB1a has an isoform-specific function in transcriptional regulation while all three isoforms share an ER-independent function to modulate proliferation.Despite the clear relationship between GREB1 expression and proliferation of breast cancer cells, the explicit mechanism by which GREB1 regulates this process remains unclear.As GREB1a is the predominant isoform in cell lines and patient samples, I focused further investigation on this isoform.Our studies indicate that knockdown of GREB1 results in growth arrest and exogenous expression of GREB1 induces cellular senescence, suggesting a dynamic role for GREB1 in the modulation of proliferation.Analysis of signaling pathways known to regulate both senescence and proliferation revealed that iv GREB1 is able to modulate signaling through the PI3K/Akt/mTOR pathway.I show that GREB1 acts through the canonical PI3K pathway to regulate PIP 3 levels and activation of Akt and downstream effectors.Importantly, growth suppression of estrogen-dependent breast cancer cells by GREB1 knockdown is rescued by expression of constitutively activated Akt.Together, these data demonstrate a novel mechanism by which GREB1 modulates signaling through the PI3K/Akt/mTOR pathway to regulate proliferation of breast cancer.These findings are critical to better understanding how ER-target genes drive proliferation of breast cancer and developing innovative therapies that act downstream of ER-signaling.v Dedication This work is dedicated to my mother, Kimberley Haines, and my brother, Kel Haines, for their unconditional love and support.I am beyond appreciative of my graduate advisor, Dr. Craig Burd.When I decided to come to OSU I had a clear idea of the type of mentor and lab environment I was looking for: approachable, hands-on, engaging, motivating, and fun.I am thankful to say I found all of those characteristics in
Author: Haines, Corinne Nicole
Institution: The Ohio State University
Language: English
Subfield: Endocrinology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7045900816