Ever since the side effects of hormone-replacement therapy (HRT) were reported in 2002, evidence has been mounting that the menopause treatment increases a woman’s risk of breast cancer. What hasn’t been resolved is how.
Two studies published today in Nature1,2 show how one ingredient of HRT, a synthetic version of the hormone progesterone called a progestin, can cause breast cancer in mice by activating the protein RANKL.
The findings also suggest that blocking this pathway with a drug already approved for osteoporosis might treat breast cancer.
Widely prescribed in the 1960s and 70s to combat menopausal symptoms such as hot flushes, HRT initially contained only a form of oestrogen. However, after studies showed that oestrogen treatment alone increased a woman’s risk of endometrial cancer, drug manufacturers added a progestin to the mix. Millions of women took the new combined therapy.
That all changed after researchers studying patients enrolled in the Women’s Health Initiative concluded that women on HRT were about 25% more likely to develop breast cancer within 5 years than women taking a placebo3. Women abandoned the treatment and breast cancer rates plummeted — in the United States by more than 6% in 2003.
“I’ve sort of looked at the HRT studies as really being a validation in humans that progestin plays a role in cancer development,” says William Dougall, scientific director of oncology and hematology research at the biotechnology firm Amgen, who is based in Seattle, Washington, and led one of the teams that linked RANKL to breast cancer.
The RANKL protein, which is part of a family of immune signalling proteins, is best known for its role in bone regeneration. RANKL activates specialized cells called osteoclasts, which break down bone and allow its calcium to be reabsorbed.
This isn’t RANKL’s only role in the cell, however. In 2000, a team led by Josef Penninger, then at the University of Toronto in Ontario, Canada, discovered that mice lacking RANKL have problems developing new breast tissue when pregnant, a process that hinges on sex hormones, including progesterone4.
Teams led by Penninger, who has since moved to the Austrian Academy of Science in Vienna, and Dougall now show that RANKL is also implicated in mouse models of breast cancer that are driven by progestin. The two teams worked independently but communicated with one another about their results. “Both of us felt that it is very important to have an independent confirmation,” Penninger says.
When Penninger’s team treated mice with a progestin called MPA, expression of RANKL in the animals’ mammary tissue sky-rocketed. Meanwhile, mice genetically engineered to lack the RANKL receptor in their mammary tissue that were given both progestin and a cancer-inducing chemical had fewer mammary tumours than normal mice after eight weeks. Penninger’s team also showed that RANKL spurs mammary epithelial cells to divide, and helps to maintain the stem cells that give rise to breast tumours.
Dougall’s team took a slightly different approach to establishing RANKL’s role in progestin-driven breast cancers. Instead of using mice that lack the protein, the researchers gave mice an antibody drug that prevents RANKL from communicating with its receptor — a treatment that had much the same effect. Mice treated with the drug, as well as MPA and a carcinogen, developed fewer mammary-tissue tumours than mice that did not receive the drug.
Dougall and Penninger agree that blocking RANKL could prevent breast cancers, or treat them in their early stages. However, unlike most basic-research findings of medical significance, translation of the RANKL findings could be rapid.
Amgen’s RANKL-blocking antibody, marketed as Denosumab, gained approval for treating osteoporosis from the US Food and Drug Administration in June. The biotech company hasn’t yet launched a clinical trial to look specifically at whether Denosumab could prevent or treat primary breast tumours, but is currently testing whether the drug prevents bone metastases in breast cancer and other tumours.
Jane Visvader, head of the Breast Cancer Laboratory at the Institute of Medical Research in Parkville, Australia, says that the drug has “enormous potential” to prevent or treat breast cancer.
“It would be really straightforward to bring this into the clinic,” agrees Cathrin Briskin, a molecular biologist at the Swiss Federal Institute of Technology in Lausanne. “It’s definitely worth trying.”
However, Briskin notes that human breast cancers are notoriously heterogeneous, and some continue to rely on sex hormones to grow, whereas others do not. “The fact that it works in mice doesn’t meant that it will work in humans, when we get to humans we need to differentiate between the different subtypes of cancer,” she says.