Upstate researchers decipher breast cancer clues in proteins

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This protein, called WDR5, is a component of the Mixed Lineage Leukemia core complex and is shown in purple/pink, bound to an inhibitor in green. The structure was determined in the lab of Michael Cosgrove, PhD, at Upstate Medical University.

BY AMBER SMITH

In the laboratories at Upstate Medical University, some breast cancer research focuses on proteins, the microscopic molecules that are present in all living organisms.

“Proteins in cells are responsible for doing much of the work within cells, including normal growth control and elimination of cells that are headed down a path to become cancer,” explains David Amberg, PhD, a professor of biochemistry and molecular biology who serves as vice president for research at Upstate.

Cancer arises because of the dis-regulation of key regulatory proteins. Their study — called proteomics — is at the forefront of cancer research. Five Upstate projects that received a share of a $250,000 grant this fall from the Carol M. Baldwin Breast Cancer Research Fund Inc. involve proteins.

In the years since the human genome was completed in 2003, many researchers have advanced the understanding of genetic influences that impact cancer. The National Cancer Institute has an Office of Cancer Clinical Proteomics Research, which says genetics “only provides us with a glimpse of what may occur as dictated by the genetic code. In reality, we still need to measure what is happening in a patient in real time, which means finding telltale proteins that provide insight into the biological processes of cancer development.”

Compared with genomic research, proteomic research has a number of unique challenges.

To begin with, a single gene can encode more than one protein. Some genes encode up to 1,000 proteins. So exponentially more proteins exist in human cells for scientists to understand.

Genes may have mutations that cause particular genetic conditions, but protein types can vary from one person to another under different environmental conditions, or within the same person at different ages or stages of health.

Also, proteins continually undergo changes. They may partner with one another to form complexes. They may bind to cell membranes to regulate membrane trafficking. The genome is relatively static.

Perhaps most confounding is the wide range of concentrations of proteins within the body. Blood contains more than a billion times greater concentration of the protein albumin, for instance, than it does of the protein interleukin-6. That makes the detection of a low abundance of proteins tricky — and cruelly paradoxical, since scientists believe the most important proteins for cancer may be those found in the lowest concentrations.

Scientists are motivated by challenges like these. They quietly chip away, making progress against breast cancer, one protein at a time.

Take a look at five projects underway at Upstate, followed by a brief explanation of proteins, enzymes and genes:

Clue: This enzyme keeps cancer cells alive

Scientists have known for 100 years that cancer cells have a metabolism that’s different from that of healthy cells. They do not depend on oxygen for energy. Instead, they rely on a chemical process called fermentation — yes, the same process used to make beer – which creates an acidic byproduct that can cause the cancer cells to die.

Stephan Wilkens, PhD, and his team in biochemistry and molecular biology want to understand that better.

Stephan Wilkens, PhD

Stephan Wilkens, PhD

They know that to prevent cell death, the cancer cells make more of an enzyme called V-ATPase, which helps rid the cells of the excess acid and stay alive.

Some breast cancers stay put and grow. Others spread quickly to other parts of the body. It’s these more aggressive cancers, it turns out, that contain greater concentrations of V-ATPase. Several laboratories, including Wilkens’ at Upstate, are exploring this phenomenon.

The Wilkens team is working with yeast cells, which allows scientists to study the mechanism and structure of the enzyme. V-ATPase is composed of 30 proteins, and it behaves differently in the kidney, for instance, than in bone, or in a cancer.

“You can’t just give a drug that inactivates the enzyme, because you would kill the cancer, but also the patient,” Wilkens explains. “We have to be more specific here, more subtle.”

Ultimately, Wilkens’ team wants to develop an agent like an antibody that would shut down certain aspects of the enzyme.

Clue: Two proteins pair up to spur tumor growth, spread

Hormonal therapy is one of the most successful and least toxic treatment approaches for patients with breast cancer. A drug called tamoxifen has been used for more than 40 years to treat breast cancers that are hormone-receptor positive – but, more than half of patients are resistant to hormone therapy or develop a resistance over time.

Mehdi Mollapour, PhD

Mehdi Mollapour, PhD

Research in the laboratory of Mehdi Mollapour, PhD, an assistant professor in the departments of urology, biochemistry and molecular biology, unraveled two key proteins called PP5 and CK2 that are involved in tamoxifen resistance in breast cancer. They act as molecular switches, controlling many biological process in the cell.

Mollapour says it appears that these two proteins are permanently “switched on” in breast cancers that are resistant to tamoxifen. His research goal is to use the proteins as targets for a new therapy that would treat tamoxifen-resistant breast cancers.

Clue: Inactivating this protein inhibits cancer cell growth

Cancer biologist Golam Mohi, PhD, focuses his research on an enzyme that exists in greater quantities in the cells of one of the most deadly breast cancers, triple-negative breast cancer. Because these breast cancer cells have no estrogen/progesterone receptors, some of the most common breast cancer medications are ineffective.

“That’s why we got interested,” Mohi says. He explained that the enzyme, Pim-1 kinase, is over-expressed in triple-negative breast cancer, “but if you knock it down, the growth of this breast cancer cell is remarkably reduced.”

Goals Mohi, PhD

Golam Mohi, PhD

His laboratory is also experimenting with a Pim kinase inhibitor. When the scientists treat the breast cancer cells with the Pim kinase inhibitor, they see a dramatic inhibition of growth of the cancer cells.

In addition to slowing the growth of the cancer cells, this Pim kinase inhibitor also seems to alter the migration or metastasis of the cancer cells, Mohi says. The next step will involve testing the efficacy of Pim kinase inhibition in animal models of breast cancer.

Mohi says his research will hopefully identify a new way to treat triple-negative breast cancers, plus provide new insights into the biology of breast cancer.

Clue: High levels of this protein lead to poor prognosis

The myosin 1e protein plays a role in how well cancer cells stick together and their ability to migrate or spread through the body. In the case of invasive breast cancer, high levels of myosin 1e correlate with a poor prognosis, according to research performed by the lab of Mira Krendel, PhD, a cell and developmental biologist.

Mira Krendel, PhD

Mira Krendel, PhD

The research team has also shown that removing myosin 1e in laboratory animals can halt tumor growth and slow the spread of cancer cells. While that sounds encouraging, Krendel said that trying to block myosin activity in someone who develops invasive breast cancer has to be done carefully because myosin 1E is required for normal kidney function.

Juntao Luo, PhD

Juntao Luo, PhD

Working together with Juntao Luo, PhD, a scientist in pharmacology, she would like to find a way to block myosin function in tumor cells, while preserving its activity in other organs.

Also, her laboratory may be able to develop the use of myosin 1e as a biomarker. It would work like this: People diagnosed with invasive breast cancer would have their myosin level tested. Finding high levels of myosin 1e would suggest a poor prognosis – which may help guide treatment decisions.

Clue: Removing this protein causes cell death

Breast cancer can be divided into four major molecular subtypes, the most common of which stands out because of the especially active nature of a protein called PAD2.

Inhibiting this protein stimulates death of the cancer cells – and scientists are trying to understand the molecular mechanics involved.

Michael Cosgrove, PhD

Michael Cosgrove, PhD

“We’re looking for ways to inhibit it, and to do that, we’ve got to figure out how it works,” says Michael Cosgrove, PhD, an associate professor of biochemistry and molecular biology.

He and his team discovered that PAD2 targets another protein complex that Cosgrove’s lab works with, called MLL1. “We need to understand how they interact at the molecular level.”

The goal is to use that information to develop a new targeted breast cancer therapy.

What are proteins?

Large, complex molecules that are essential for the structure, function and regulation of the body’s tissues and organs. Proteins are made up of long chains of amino acids – some of which are made by the body, others that come from the foods we eat. They exist in all living organisms.

What are enzymes?

Special types of proteins that are catalysts for a variety of specific biochemical reactions. Their actions can be regulated by temperature, pH level, hormones and other factors. Various enzymes exist in all living organisms.

What are genes?

The physical and functional unit of heredity. Thousands of genes made up of DNA coil together to form each chromosome in all living things, and in humans they are contained in the nucleus of cells. Each gene has instructions for making one or more proteins.

Layout 1This article appears in the winter 2016 issue of Cancer Care magazine.

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