Researchers at the University of Alabama at Birmingham (UAB) recently revealed a potential new therapy for a subtype of breast cancer, the HER2+ (human epidermal growth factor receptor 2). The study was recently published in the journal Breast Cancer Research and Treatment and is entitled “PARP1 and phospho-p65 protein expression is increased in human HER2-positive breast cancers.”
It is estimated that, apart from skin cancer, breast cancer is the most commonly diagnosed cancer among American women, affecting more than 230,000 individuals every year. The death rate in women associated with breast cancer is higher than any other cancer, except for lung cancer. 1 in every 8 American women is predicted to develop invasive breast cancer over the course of her lifetime.
There are five different subtypes of breast cancer: HER2-enriched (or HER2+), triple negative (or basal), luminal A, luminal B and unclassified. Each of these subtypes is characterized by a distinct disease, biology, treatment response and progression. A deeper understanding of these differences will allow a more effective and personalized treatment.
Previous studies have shown that triple negative breast cancers express high levels of the DNA repair enzyme PARP1 [poly (ADP-ribose) polymerase 1] and that they are sensitive to PARP inhibitors. UAB researchers have reported in 2012 that HER2+ breast cancer cells are also sensitive to PARP inhibitors by interfering with NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway, which is linked to DNA transcription, the first step in gene expression where the DNA is copied into RNA. Abnormal NF-kappaB regulation has been associated to cancer development and aggressiveness.
In the present study, the research team analyzed breast cancer tissue samples from 307 patients who had been diagnosed with either HER2+ (93 patients), triple negative (132 patients) or luminal (82 patients) breast cancers at UAB between 1999 and 2012. The levels of PARP1protein were assessed, together with phopho-p65 protein, which is a marker of activated NF-kappaB.
Researchers found that HER2+ and triple negative breast cancers, but not luminal cancers, expressed high levels of PARP1. HER2+ cancers were found to be three times more likely than HER- to have high PARP1 levels. The team also found that HER2+ cancers had a higher expression of phospho-p65 protein in comparison to HER- cancers. A direct correlation between PARP1 and phospho-p65 was found, suggesting that these two proteins are expressed in a coordinated manner.
The team concluded that HER2+ breast cancers have high expression of PARP1 and phospho-p65 proteins, and that PARP inhibitors could be considered a viable therapy for this type of breast cancer that has a fairly poor prognosis.
“Whether elevated PARP1 and phospho-p65 levels can serve as a potential marker of PARP inhibitor sensitivity should be tested in future clinical trials,” concluded the authors. Different PARP inhibitors from several manufacturers are currently being tested in clinical trials, and the U.S. Food and Drug Administration (FDA) has already approved one PARP inhibitor (Lynparza or olaparib) for patients with advanced ovarian cancer.