Scripps Florida Scientists Uncover Inflammatory Circuit That Triggers Breast Cancer
Although it’s widely accepted that inflammation is a critical underlying factor in a range of diseases, including the progression of cancer, little is known about its role when normal cells become tumor cells. Now, scientists from the Florida campus of The Scripps Research Institute have shed new light on exactly how the activation of a pair of inflammatory signaling pathways leads to the transformation of normal breast cells to cancer cells.
The study, led by Jun-Li Luo, an assistant professor at Scripps Florida, was published online before print by the journal Molecular Cell on February 23, 2012.
The scientists’ discovery points to the activation of a self-sustaining signaling circuit that inhibits a specific RNA, a well-known tumor suppressor that helps limit the spread of cancer (metastasis). Therapies that disable this circuit and halt this miRNA repression could have the potential to treat cancer.
The Spark that Ignites Trouble
In the new study, scientists identified the specific pathways that transform breast epithelial cells into active cancer cells.
The researchers found immune/inflammatory cells ignite the transient activation of MEK/ERK and IKK/NF-kB pathways; the MEK/ERK pathway then directs a consistent activation of a signaling circuit in transformed cells. This consistent signaling circuit maintains the malignant state of the tumor cells.
Risk factors
While we do not yet know exactly what causes breast cancer, we do know that certain risk factors are linked to the disease. A risk factor is something that affects your chance of getting a disease such as cancer. Different cancers have different risk factors. Some risk factors, such as smoking, drinking, and diet are linked to things a person does. Others, like a person’s age, race, or family history, can’t be changed.
But risk factors don’t tell us everything. Having a risk factor, or even several, doesn’t mean that a woman will get breast cancer. Some women who have one or more risk factors never get the disease. And most women who do get breast cancer don’t have any risk factors (other than being a woman and growing older). Some risk factors have a greater impact than others, and your risk for breast cancer can change over time, due to factors such as aging or lifestyle.
Although many risk factors may increase your chance of having breast cancer, it is not yet known just how some of these risk factors cause cells to become cancer. Hormones seem to play a role in many cases of breast cancer, but just how this happens is not fully understood.
Luo compares this process to starting a car - a car battery starts the engine much like the transient signal activation turns on the consistent signal circuit. Once the engine is started, it no longer needs the battery.
The scientists go on to show that the initial activation of these pathways also activates IL6, a cytokine involved in a number of inflammatory and autoimmune diseases, including cancer. IL6 acts as a tumor initiator, sparking the self-sustaining circuit in normal breast cells necessary for the initiation and maintenance of their transformed malignant state.
In establishing that self-sustaining signal circuit, IL6 represses the action of microRNA-200c, which is responsible for holding down inflammation and cell transformation. Since enhanced microRNA-200c expression impairs the growth of existing cancer cells and increases their sensitivity to anti-tumor drugs, compounds that disable microRNA-200c repression have the potential to act as a broad-spectrum therapeutic.
Smoking triggers breast cancer
Women who smoke increase their exposure to a toxic metal which scientists have now found is directly linked to a higher risk of breast cancer.
Exposure to cadmium is also linked to the risk of a woman’s unborn child developing breast cancer, according to the new study.
Cadmium is a naturally occurring metal found in soil, rocks and water and is also used in batteries.
People could be exposed through food grown in contaminated soil or fish from tainted water. However the greatest exposure comes from smoking, which doubles the daily intake of cadmium.
Exposure to cadmium has already been linked to lung cancer, lung disease, kidney damage and possibly prostate cancer.
Interestingly, the new findings dovetail with the “multiple-hits theory” of tumor formation, which posits that once normal cells in the human body accumulate enough pre-cancerous mutations, they are at high-risk for transformation into tumor cells. While the newly described initial pathway activation is momentary and not enough to cause any lasting changes in cell behavior, it may be just enough to tip the cell’s transformation to cancer, especially if it comes on top of an accumulation of other cellular changes.