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Discoveries by Upstate researchers could impact breast cancer treatments

A team of researchers and doctors at Upstate Medical University, led by Leszek Kotula, MD/PhD, have  published ground-breaking findings in breast cancer research.

The translational study, titled “ABI1 based expression signature predicts breast cancer metastasis and survival” was published in the prestigious journal Molecular Oncology in December.

“The study carries significant potential to be utilized in clinical diagnosis in the future,” Kotula said. “Our paper is producing a new kind of paradigm. By analyzing the primary tumor gene expression, we can predict, with very high potential to be correct, whether this tumor metastasizes in the future, in ten years, in 20 years, based on the collaboration of seven genes.”

Breast cancer is the second most common cancer in women after skin cancer, and metastatic breast cancer is often incurable. While mammograms can detect tumors, there is currently no way to precisely predict metastatic potential of a tumor, or the likelihood it will spread to another part of the body such as the bones, lungs, brain and liver.

That’s where this research can have an impact.

Kotula’s research centers on the role of seven genes in the development of metastatic breast cancer, and the ABI1 is the key gene in that expression signature.  It one of the proteins of the WAVE complex, which is a multi-protein unit responsible for making cells invasive.

Kotula, an associate professor of urology, biochemistry and molecular biology at Upstate, discovered the ABI1 gene in 1998. In 2001, he published the first study on the gene’s role in prostate cancer. Subsequent work from his lab delineated mechanisms of prostate tumor progression associated with ABI1. In prostate cancer, the presence of the gene inhibits cancer growth, while low levels or the absence of it leads to prostate cancer.

It’s the opposite in breast cancer. High levels of ABI1, or an overexpression, corresponds with poor survival and shorter relapse time in patients with primary breast cancer tumors.

“I started breast cancer (research) because I was puzzled by the discordant function of the protein/gene in different types of cancer,” Kotula said. “It’s very interesting. We are coming to an understanding about this gene’s role, and it all makes sense now. But we need to do a lot of research. It’s a homeostatic gene. Too much is bad, too little is bad. You need to have a certain level. The homeostatic genes like ABI1 often play a critical role in drug treatment sensitivities and resistance.”

In the breast cancer study, the team translated observations from a mouse model to genetic information of human breast cancer patients.  Kotula’s student Angelina Regua (who is now a postdoctoral fellow at the Wake Forest Cancer Center) confirmed the observation from breast cancer patients in the novel mouse model with breast cancer metastasis.

Regua disrupted, or knocked out, the ABI1 gene in mice with breast cancer. When both copies of the gene were knocked out, there was almost no metastasis. When one copy of the gene was knocked out, tumor progression slowed. The mouse model established that ABI1 is the critical gene responsible for metastasis to the lungs.

Then they analyzed human gene information using data provided by The Cancer Genome Atlas (or TCGA) and predicted there are seven genes that predict metastatic potential. Upstate’s Vladimir Kuznetsov, PhD, a professor of urology, biochemistry and molecular biology, and his group of students in collaboration with Kotula’s lab used advanced bioinformatic and novel biostatistics approaches to develop a 7-gene prognostic ABI1-based gene signature for breast cancer metastasis.

The work was a collaborative effort between the Kotula and Kuznetsov Laboratories, Abirami Sivapiragasam, MD, from Upstate’s Department of Medicine, and Isabelle Bichindaritz, MD from SUNY Oswego.

“I love to collaborate,” Kotula said. “I talk about my science to everybody, the door to my lab is open to collaborators and new ideas. Translational science requires multidisciplinary collaborations to make meaningful progress. This is possible in our Urology department, led by the surgeon-scientist Dr. Gennady Bratslavsky.”

The study, which began in 2015 and has cost about $400,000 thus far, was mainly funded by the Carol M. Baldwin Breast Cancer Research Fund of CNY, the Upstate Cancer Center Pilot Grant (Connolly Fund), and the National Cancer Institute. The Upstate Foundation Dawn K. (Smith) Steber Endowment for Cancer Research also contributed to the study.  

Kotula says the paper generated potential for multiple future studies, including a Phase I Clinical trial, where researchers will do gene sequencing on tumors of breast cancer patients, follow them for metastasized tumors, looking for the role of the ABI1.

The prognostic signature will help advance better drug targets and diagnosis, bringing science one step closer to a cure.

“People are treated right now with certain drugs,” Kotula said. “Many of them fail to prevent or cure metastases. This is the next biggest problem to solve, why they fail. We want to understand how ABI1-signature genes behave under the treatment. The treatment that will alter the signature will be evaluated for metastatic potential with the hope to prevent it.”