THE ESTROGEN RECEPTOR IS THE CENTER OF IT ALL
Roughly 175,000 women in the US annually are diagnosed with breast tumors that express proteins called estrogen receptors (ER) that bind the hormone estrogen, which drives tumor growth. These women are eligible for treatment with "anti-estrogens" to block ER.
Despite the success of these drugs, >20% of women treated with anti-estrogens will experience tumor recurrence within 10 years of starting treatment.
Our lab endeavors to understand and overcome anti-estrogen resistance by advancing our knowledge of ER biology.
EBCTCG, Lancet, 1998
A summary of our research
This diagram explains why we use anti-estrogens - drugs that block the action of the estrogen receptor (ER) - to treat breast cancer patients.
Androgens are converted by the enzyme 'aromatase' to estrogens. Estrogen then activates ER, which acts to regulate gene expression and drive tumor growth.
Using drugs like tamoxifen or fulvestrant directly blocks ER activity, while aromatase inhibitors block the production of estrogen. Both classes block ER activity, and suppress tumor growth.
Anti-estrogen therapies work - the risk of breast cancer recurrence is cut in half...
...but for >20% of patients taking anti-estrogens, cancer will recur within 10 years of beginning treatment. This risk of breast cancer recurrence after treatment continues for at least 20 years.
New therapies for recurrent breast cancer are available, but novel approaches to prevent and overcome anti-estrogen resistance are an urgent clinical need.
The Sikora Lab is currently taking two primary approaches to address this issue:
Studying how ER interaction with the genome and control of target genes is regulated in invasive lobular carcinoma of the breast (ILC).
Investigating how unique ER signaling pathways in ILC drive anti-estrogen therapy response and resistance.
The Sikora Lab Playbook
Sometimes it's easier to see things when you put it terms of the X's and O's.
estrogen receptor biology in ilc
Invasive lobular carcinoma of the breast (ILC) is a subtype of breast cancer with unique biological features, including a characteristic "single-file" infiltrative pattern (see right). This, and related clinical features, create unique issues in the management of ILC, but there are currently no specific therapeutic options for the treatment of ILC patients. However, recent molecular and clinical studies confirm that ILC is a unique biological subtype of breast cancer, and that dedicated efforts to understand the biology of ILC are needed to improve ILC patients outcomes.
Our lab has identified that ER has unique functions in ILC cells which drive ILC response and resistance to anti-estrogen therapies. Understanding these functions is critical to developing new therapeutic strategies for ILC patients
WANT TO LEARN MORE ABOUT ILC? | Lobular Breast Cancer Alliance | ILC Review Collection | ILC Symposium Summary
FACTORS DRIVING UNIQUE ER FUNCTIONS IN ILC
The functions of ER in ILC cells are unique versus other breast cancers - ER regulates unique target genes in ILC cells, and ER is not inhibited by anti-estrogens including tamoxifen in ILC cells (Sikora, Cancer Res 2014). ILC-specific ER functions may be mediated by the activities of other nuclear factors, specifically transcription factors (i.e. proteins binding DNA to direct gene expression programs) or co-regulators (i.e. proteins associating with transcription factors to recruit regulatory complexes of modify DNA).
(A), In most breast cancer cells, an ER binding site (red star) is inaccessible; the regulated gene is not activated. (B), In ILC, a novel transcription factor (TF) allows access to the site and ER regulation of the target gene. (C), ER may be insufficient to recruit transcriptional machinery to a target gene in most breast cancer cells, but in in ILC (D), a novel ER co-regulator (CoR) recruits the PolII complex to activate expression.
Toward this goal, we used proteomics and an unbiased siRNA screen to profile transcriptional co-regulators of ER in ILC. Unexpectedly, we found DNA damage response (DDR) protein MDC1 (mediator of DNA damage checkpoint 1) as an ILC-specific ER co-regulator. We are working to understand how MDC1 regulates ER function in ILC cells, and how these co-regulator functions interplay with the canonical roles of MDC1 in DDR. Sottnik & Bordeaux, Molecular Cancer Research 2021.
OUR BIG QUESTIONS
We are working to understand how the ILC-specific functions of co-regulators like MDC1 alter or dictate the genomic context for ER function during ILC tumorigenesis, hormone and therapy response, and disease progression.
How does MDC1 re-model or re-define the genes that ER regulates in ILC cells?
What mediates or allows the ER:MDC1 partnership in ILC, but not other cells?
What transcriptional or epigenomic proteins cooperate with ER:MDC1?
How does MDC1 co-regulator activity mediate or permit anti-estrogen resistance?
How does ILC-specific ER:MDC1 activity impact DNA repair capacity?
Does MDC1 activity have distinct roles across the progression of ILC?
WNT4 IS a unique SIGNALING MOLECULE AND eR effector in ilc
In our initial study characterizing anti-estrogen response and ER transcriptional targets in ILC models, we identified the Wnt ligand WNT4 as a unique, ILC-specific ER target gene (Sikora, Cancer Res 2014). WNT4 is a critical mediator of normal mammary gland development, but ILC cells co-opt this mechanism by placing WNT4 directly under the control of ER. We demonstrated that WNT4 is necessary for ILC cells to grow in response to estrogen, and that WNT4 is also involved in the development of anti-estrogen resistance (Sikora, Breast Cancer Res 2016).
Understanding how WNT4 controls ILC cell growth and anti-estrogen resistance, and how the WNT4 gene is regulated in ILC cells, will identify new therapeutic targets to develop as strategies to improve anti-estrogen response or block anti-estrogen resistance.
However, we WNT4 does not follow the current paradigm of Wnt signaling. While Wnt ligands are typically secreted to activate paracrine/autocrine signaling, we found WNT4 can bypass normal secretory pathways and can activate signaling as an intracellular signaling molecule. Rao, JBC 2019.
Work is ongoing to understand how intracellular WNT4 initiates and propagates intracellular signaling, but we found that downstream, WNT4 controls mTOR signaling and is critical for mitochondrial function and cellular metabolism. Shackleford, Cancers 2020.
OUR BIG QUESTIONS
Understanding the mechanisms by which ER controls WNT4 expression and the signaling pathways downstream of WNT4 are major focuses of the Sikora Lab.
What allows WNT4 to be retained intracellularly, and what makes WNT4 protein trafficking unique versus other Wnt proteins?
What is the intracellular "receptor" that initiates WNT4 signaling?
In what tissues and disease states is intracellular WNT4 signaling active?
What differentiates cell states that support paracrine versus intracellular WNT4 signaling?
What allows ER to control WNT4 expression specifically in ILC cells?
How is the "normal" WNT4 pathway co-opted to drive ILC development and progression?
How does WNT4 drive anti-estrogen resistance?
THANK YOU TO OUR SUPPORTERS
We are grateful for current and previous research grant support.
National Cancer Institute | University of Colorado Anschutz Medical Campus School of Medicine | American Cancer Society | Cancer League of Colorado | CU Anschutz RNA Bioscience Initiative | Denver Chapter of Golfers Against Cancer | Univ. of Colorado Cancer Center Tumor Host Interactions Program | Dept. of Defense Breast Cancer Research Program | Dynami Foundation
Special Thanks to our philanthropic supporters
We are immensely grateful to receive support from the patient and advocate community that we strive to serve.
Thank you to Leigh Pate, Lori Petitti, Mary Vaughan, Debbie Milburn, Karen Simmons, Ian Goldberg, Shana Kucharek, Christian Moreno, and Janice Carter for their generous support of our research projects, and supporting the lab directly through the Lobular Breast Cancer Research Fund.