Researchers at the University of Michigan have unveiled how two distinct types of mutations to the forkhead box A1 (FOXA1) gene, a common driver of prostate cancer, drive different mechanisms of tumor formation and treatment resistance in a mouse model. Their findings, published in Science, open the door for precision medicine strategies that address mutation-specific drivers of disease in patients with this form of cancer.
“This is the first in vivo demonstration of FOXA1 as an initiator of prostate cancer,” said Arul Chinnaiyan, MD, PhD, professor of pathology and urology at the University of Michigan Rogel Health Cancer Center. “Prior studies relied on cell lines, but our mouse models provide definitive evidence of its causal role in tumor development.”
The FOXA1 gene encodes a transcription factor that is directly involved in the expression of prostate-specific genes. This gene is one of the most frequently altered in prostate tumors, with 10% to 40% of prostate cancer patients carrying a FOXA1 mutation. However, there is still limited knowledge about how exactly mutations in this gene drive cancer.
In a previous study, Chinnaiyan and colleagues had identified three structural classes of FOXA1 mutations that are associated with different patient outcomes. In the current study, the team has dug deeper to find the molecular mechanisms that two of these mutation types employ to drive tumor growth and resistance. “This study goes further by revealing how distinct alterations within the same gene can initiate disease in early stages or confer resistance in late-stage, therapy-refractory tumors,” said Chinnaiyan.
The study found that class 1 mutations in the FOXA1 gene, which are more commonly reported in cases of primary prostate cancer, work together with mutations that inactivate p53 to drive the formation of new tumors that are sensitive to hormone therapy. This mechanism is mediated by the co-activation of mTORC1/2 and androgen receptor (AR) signaling pathways.
“Modeling primary prostate cancer’s response to androgen withdrawal in mouse models has been challenging,” said Abhijit Parolia, PhD, assistant professor of pathology at the University of Michigan Rogel Health Cancer Center. “We demonstrated that prostate tumors driven by Class 1 mutations require continuous androgen supply for growth and survival, establishing the FOXA1/p53 mouse model as a valuable preclinical system.”
On the other hand, class 2 mutations, which are more common in patients with metastatic cancer, are not able to promote tumor growth on their own. Instead, they were found to access latent DNA sites to reprogram fully differentiated luminal cells to acquire a more stem-like state through the activation of KLF5 and AP-1 pathways. This mechanism results in tumors that are resistant to standard hormone therapy. “Activation of these sites turn on genes that drive adaptation to androgen blockade, enabling cancer’s escape from therapy,” Parolia explained.
When treating prostate cancer, the standard first line treatment is androgen deprivation therapy, a form of hormone therapy that reduces the levels of male sex hormones such as testosterone to stop the growth of the tumor. However, many patients that initially respond to this form of treatment can develop resistance against it over time. These results showcase how different types of mutations within the same gene can result in different treatment outcomes and unlock new information that can be used by practitioners to make informed decisions on the best course of action for each individual case.
