City of Hope investigators are a step closer to identifying the molecular changes that occur when prostate cancer advances from a mild to a more aggressive stage.
Janni Mirosevich, Ph.D., assistant research scientist in the lab of Richard Jove, Ph.D., professor and chair of the Department of Molecular Medicine, recently showed at an American Urological Association (AUA) meeting that differences in the expression of two important proteins signal the transition from treatable to more aggressive prostate tumors.
At first, prostate tumor cells need male sex hormones, known as androgens, to grow. One treatment option to slow growth or shrink a tumor before surgery is to reduce androgen levels in the body — either surgically or through therapy. Over time, though, many prostate tumors start growing independent of androgens, eliminating that treatment option.
No one knows exactly how tumor cells make that transition, but Mirosevich’s findings implicate two members of the forkhead box (Fox) protein family, so named because mutations in the fruit fly forkhead gene result in an unusual, spiked-head appearance.
The group zeroed in on two Fox proteins, Foxa1 and Foxa2. “Foxa proteins are necessary in the normal development of lung and liver, and for prostate tissue, where Foxa1 regulates important prostate-specific genes,” explained Mirosevich.
Mirosevich and colleagues examined mice genetically engineered to develop prostate cancer (developed by Robert J. Matusik, Ph.D., of Vanderbilt University) and found unusually high levels of Foxa1 protein in abnormal prostate cells that formed prostate intraepithelial neoplasia lesions — lesions that may precede cancer. These lesions did not express the other protein, Foxa2.
In contrast, mice with another aggressive, androgen-independent prostate cancer called neuroendocrine carcinoma did show high Foxa2 expression in tumors. “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.”
But does Foxa2 expression in androgenindependent tumors promote more aggressive forms of cancer? One experiment suggested that it might.
The investigators tinkered with the molecular on/off switch of the gene that encodes prostate-specific antigen (PSA) in human prostate cancer cells. They found that androgens together with Foxa1 could turn the gene on. However, even without androgens, the other protein, Foxa2, could switch on the PSA gene all by itself. That means that Foxa2 — unlike Foxa1 — can stimulate androgenindependent gene expression.
If further research bears it out, Foxa2 may be a therapeutic target for androgen-independent tumors.
In collaboration with the Division of Urology & 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 Division 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.”
Jove, Matusik, and Wilson were co-authors of the AUA poster, which was presented in May, as were City of Hope medical oncologist Przemyslaw Twardowski, M.D., and Nan Gao, Ph.D., and Aparna Gupta, M.Sc., of Vanderbilt, and Scott Shappell, M.D., Ph.D., of the Oppenheimer Urologic Reference Laboratory.
The Department of Defense funded the work through a grant to Mirosevich.