A member of the Hox family of transcription factors, HOXB13, may contribute to tumor progression in some ovarian cancers and might serve as a biomarker for cancer aggressiveness, according to a study in the Oct. 23 Proceedings of the National Academy of Sciences. Ovarian cancer is notoriously difficult to detect, and an estimated one in 71 women will develop the disease in her lifetime, according to the National Cancer Institute.
The lab of Dennis Sgroi, HMS associate professor of pathology at Massachusetts General Hospital, usually investigates the role of HOXB13 in breast cancer. Many breast tumors rely on the binding of estrogen to the estrogen receptor (ER) to promote tumor growth. The antihormonal drug tamoxifen competes with estrogen for the ER, thereby impeding tumorigenesis.
In a study three years ago, Sgroi and his colleagues observed that HOXB13 was highly expressed in aggressive ER-positive breast cancers that do not respond to tamoxifen.
Since the ovary, like the breast, is hormonally regulated, Sgroi’s lab joined forces with the ovarian cancer lab of Sandra Orsulic, an HMS assistant professor of pathology at MGH, to determine whether this drug resistance or tumorigenesis was linked to the Hox protein in the ovary. “We thought, ‘Maybe HOXB13 plays a role in the ovarian neoplasia, too,’” said Sgroi. “Perhaps this gene is playing a role in resistance to tamoxifen.”
The two labs reconfirmed that HOXB13 is highly expressed in a subset of ovarian cancer cases, but has little or no expression in normal ovarian tissue. When they knocked down HOXB13 in human ovarian cancer cell lines, the researchers found reduced tumor colony formation.
Sgroi and Orsulic, co–senior authors on the paper, and their colleagues also found that human cells with an ectopic expression of HOXB13 showed other telltale signs of cancer: spindlelike morphology, loss of contact inhibition accompanied by three-dimensional and migratory growth, a reduced rate of cell apoptosis, and an enhanced rate of proliferation. Notably, ectopic expression of HOXB13 resulted in decreased sensitivity to tamoxifen-induced apoptosis.
Orsulic developed two mouse cell lines with mutations commonly seen in ovarian cancer, including alterations in p53, c-myc, K-ras, and Akt.
“The only difference in [the mouse cell] lines is that one has Akt and one has ras. When we put HOXB13 into the one that has ras, we had increased tumor growth,” said Sgroi. “In Akt, we did not see tumorigenesis. Somehow HOXB13 collaborates with ras.”
Until HOXB13’s role in relation to ER–positive ovarian cancer is delineated, both Sgroi and Orsulic suggest that the protein can be used as a biomarker, reflecting its role as a functional regulator of antihormonal resistance in human ovarian cancer.
The researchers are now investigating the way HOXB13 interacts with ras in the context of antihormonal therapy with drugs like tamoxifen.
