Around 80% of all breast cancers fall into the category of hormone-receptor-positive (HR+) cancers. Tumor growth in these cancers is fueled by the presence of naturally occurring human sex hormones like estrogen and progesterone.
Drugs like Tamoxifen, Letrozole, and Anastrozole help treat HR+ breast cancers by suppressing the production of estrogen in the patient’s body. However, in certain advanced forms of hormone-driven cancers, these drugs are rendered ineffective by mutations in a protein called FOXA1.
For more than 30 years, researchers have studied the FOXA family of proteins due to their critical role in important biological processes. FOXA1 was of particular interest because of its involvement in cancer drug resistance.
As it seemed to lack suitable surfaces that drug molecules can bind and target, FOXA1 was long considered undruggable by researchers. A team of scientists at the Scripps Research Institute, a non-profit medical research facility in San Diego, California has proven that this is not true.
This breakthrough, reported in Molecular Cell, could have major implications for the treatment of drug-resistant forms of breast and prostate cancer. In this article, we examine the history and role of FOXA1 and why the Scripps Research study could prove monumental.
What is FOXA1 and Why is it So Important?
In the human body, a transcription factor (TF) is a protein that helps control the release of genetic data inside the DNA. By binding to specific sections of the DNA, the TF can turn specific genes on and off, and ensure that key processes like cell growth and cell differentiation take place at the right place and time in the body.
The FOXA1 protein belongs to the Forkhead Box (FOX) family of transcription factors. While the first FOX proteins were identified in fruit flies, the FOXA subfamily was first discovered in lab rats in the early 1990s.
In their healthy states, the FOXA proteins have the following main functions in the human body:
- Ensuring the proper development of major organs like the liver, lungs, and pancreas
- Controlling the metabolism of glucose and fats in the body
Out of the three known FOXA proteins, FOXA1 is the one that has been strongly implicated in the growth of HR+ breast cancers. In its altered state, the gene is also found in at least 10% of all prostate cancer cases.
The Role of FOXA1 in Breast Cancer
Inside our cells, the DNA is tightly packed away in a package called the Chromatin. Ordinary TF proteins cannot directly access the DNA strands inside the chromatin. They have to wait until the chromatin is “opened up” by a special type of TF protein called “pioneer factor.” FOXA1 is a pioneer factor that opens up specific sections of the DNA for other TF proteins.
One of the transcription factors that rely on FOXA1 is the estrogen receptor alpha or the ERα protein. Found all over the body, ERα binds readily to estrogen to get activated. Once activated, it seeks out DNA strands to trigger genes that promote cell growth and proliferation.
In a healthy body, the interplay between FOXA1 and ERα helps ensure the proper growth and maintenance of breasts, uterus, ovary, male reproductive organs, bones, and even the central nervous system and the brain.
However, in certain HR+ breast cancer tumors, the disease can hijack this process for survival. These cancer cells often contain the ERα protein receptors that effectively bind with estrogen produced by the body’s ovaries and adrenal glands.
When the activated ERα receptors get access to specific chromatin regions, they will turn on growth genes linked to estrogen. This helps the cancer cells reproduce at aggressive rates, increasing the chances of tumor growth and metastasis.
And the protein that facilitates this entire process is FOXA1. Mutated and abnormally high levels of FOXA1 signaling is a common sight in many breast cancers that rely on ERα proteins (called ER+ cancers). Conversely, removing FOXA1 can reduce the cancer’s chances of successful growth:
“If we get rid of FOXA1, the estrogen receptor can’t interact with the chromatin. It just floats around in the nucleus,” explains Professor Jason Caroll, Cambridge University, in his European Journal Prize Lecture from 2016.
Implications of FOXA1 for Hormone Therapies
Hormone therapies, also called endocrine treatment, are quite effective against ER+ breast cancers. Since these cancers rely heavily on estrogen to trigger tumor growth, blocking access to the hormone can help prevent the cancer from growing or spreading to other parts of the body.
Several endocrine treatment pathways exist, out of which the following are the most common/popular:
- Selective Estrogen Receptor Modulators like Tamoxifen block the estrogen receptors in the cancer cells
- Aromatase inhibitors like Anastrozole block the production of estrogen from androgen in the adrenal glands
While Tamoxifen is primarily used to treat breast cancers in pre-menopausal women, Anastrozole and other aromatase inhibitors are more effective in post-menopausal breast cancer patients. You can learn more about the two drugs in this YouTube video featuring breast cancer specialist Hal Burstein, MD, PhD.
Across both categories, mutations in FOXA1 proteins have been linked to increased resistance to hormone therapies. When high levels of FOXA1 signaling occur, it can reduce the positive impact of the drugs by giving the cancer improved access to estrogen.
The Scripps Study Offers a Ray of Hope
The Scripps research team was led by co-authors Benjamin Cravatt and Michael Erb. Using a cutting-edge technique called activity-based protein profiling (ABPP), they discovered a hitherto hidden small molecule binding site on FOXA1.
When the research team experimented with the site on FOXA1, they made another encouraging discovery: binding molecules can change the DNA sequences targeted by FOXA1. However, there is a catch – you can only attach small molecules to the protein if the molecule is already attached to a DNA sequence.
Regardless, given the extreme rarity of binding sites on transcription factors, the FOXA1 breakthrough is an encouraging sign for the future of cancer research. Apart from the promise of drugs that can block FOXA1 and improve breast cancer treatments, the success of the ABPP technique could lead to additional breakthroughs with other cancer-linked proteins as well.
