Science Editor

Receptor activator of NF-kappaB, or RANK, and its ligand RANKL are well-known players in bone density. RANK activates osteoclasts, which are critical for breaking down bone; Amgen Inc.'s denosumab (Prolia), which prevents this activation by binding to RANKL, was recently approved for the treatment of osteoporosis and is under review for the treatment of skeletal-related events in cancer. (See BioWorld Today, Aug. 2, 2010, and June 2, 2010.)

In the case of skeletal-related events, denosumab's relationship to cancer is indirect: Metastases destroy bone, and denosumab, via its inhibition of RANKL, strengthens it.

But back-to-back studies published this week showed that targeting RANKL has direct effects on hormone-driven breast cancers as well – "the first observation," William Dougall told BioWorld Today, "that the pathway plays a role in tumorigenesis directly."

The effects of inhibiting RANKL on breast tumor development appear to be "completely separate from the bone aspect" of the pathway, Dougall said.

Dougall is a scientist at Amgen and senior author of one of the two papers, which both appeared in the Sept. 29, 2010, online edition of Nature.

Both groups "used a different approach to come to the same conclusion," namely that RANK ligand plays a role in breast cancer. Amgen's team used a combination of transgenic animals and pharmacological inhibition of RANKL, while the other research group, which consisted of a multinational team led by Austrian Josef Penninger, also knocked out RANKL.

"There was some interesting biology with respect to the pathway" suggesting it might be involved in breast tissue development, Dougall said. Specifically, Penninger's group had demonstrated that RANKL knockouts don't develop as much new breast tissue as normal animals when they are pregnant. And so Dougall's team induced breast cancer in mice by applying a mix of progesterone and a carcinogen.

Such treatment induced the expression of RANK ligand, and led to the formation of primary breast tumors and metastases. Transgenic mice with high levels of RANK had higher levels of tumor burden than normal mice, and treating the animals with a RANKL inhibitor prevented the development of such tumors, to a degree.

The findings also offered an explanation for how hormone replacement therapy, which was once widely prescribed for postmenopausal women, increases the risk of breast cancer. Epidemiological studies had shown that hormone replacement therapy increases such risk, but not how.

In their studies, Dougall's and Penninger's groups found that progesterone seems to trigger RANKL expression in breast tissue; that in turn leads to increased cell division and makes the cells resistant to programmed cell death. It also appears to affect breast cancer stem cells.

RANKL "seems to affect early events" in breast tumor development, Dougall said. But RANKL inhibition is likely to be not just useful for prevention. In transgenic animals with high levels of RANK, inhibition did not affect the onset of tumors and, "still had an effect on tumorigenesis and metastasis." Animals treated with RANKL inhibitor had fewer primary tumors, and fewer metastases to the lung.

Dougall's team is currently looking into the therapeutic possibilities of RANK ligand inhibition in more detail. In a prepared statement, a member of Penninger's team said that "we hope . . . medical trials using denosumab can be started in the near future to test whether the mouse studies can be directly translated to human breast cancer."

And possibly other hormone-driven cancers as well. Though there is presently no hard data to back it up, Dougall said that "we think that there are other factors," such as parathyroid hormone-related protein and prolactin, that may also induce RANKL expression.