Outfoxing an elusive quarry
Unfortunately, over time, many prostate tumors “learn” to grow without these hormones, eliminating hormone therapy as a treatment option and signaling an aggressive turn for the cancer. These prostate cancers are known as androgen-independent tumors. (Male hormones are called androgens.)
Janni Mirosevich, Ph.D., assistant research scientist in the lab of Richard Jove, Ph.D., director of Beckman Research Institute and professor in the Division of Molecular Medicine, is studying how that shift happens. The answers may lead to new therapies for these aggressive tumors.
photo: PAULA MYERSJanni Mirosevich
Mirosevich recently found that differences in the levels of two important proteins that play a role in the disease signal the transition from treatable to more aggressive prostate tumors.
Mirosevich’s findings implicate two members of the forkhead box protein family, called Fox for short.
The scientists zeroed in on two Fox proteins in particular, Foxa1 and Foxa2. They examined mice that had been genetically engineered to develop prostate cancer and found unusually high levels of Foxa1 protein in abnormal prostate cells that formed what are called prostate intraepithelial neoplasia lesions. These lesions may precede cancer. The scientists did not find high levels of the other protein, Foxa2, in these lesions.
In contrast, mice that had another aggressive, androgen-independent prostate cancer called neuroendocrine carcinoma did show high levels of Foxa2. “Mice with neuroendocrine tumors develop metastatic lesions,” said Mirosevich. “Patients with pure neuroendocrine tumors have very poor prognosis — these tumors are the ones that frequently metastasize.”
That led scientists to suspect that Foxa2 was somehow linked to the cancers’ aggressiveness. And further experiments showed that Foxa2 — unlike Foxa1 — can interact with prostate cells without having androgens around.
Together with the Department of Urology and Urologic Oncology’s Laura Crocitto, M.D., and Timothy Wilson, M.D., Pauline and Martin Collins Family Chair in Urology, and Huiqing Wu, M.D., in the Department of Anatomic Pathology, Mirosevich is now examining Foxa proteins in biopsy specimens from prostate cancer patients.
So far, human data mirror mouse findings. “We found Foxa2 expressed in some high-grade cancers, suggesting that those tumors are progressing to neuroendocrine cancers,” Mirosevich said. “This suggests that Foxa2 is associated with cancer progression.”
If further research bears it out, Foxa2 might be a target for much-needed therapies to fight androgen-independent prostate cancer — and allow physicians and patients to outfox the most common cancer among men.