Australian researchers have determined that triple-negative breast cancers are two distinct diseases that likely originate from different cell types, which could explain why survival prospects for women with this type of breast cancer are either very good or very poor.

Breast_CancerID4+ Stem cells are in red, luminal cells in green and all cells are marked with blue nuclear dye. Courtesy of Garvan Institute of Medical Research.

About 15% of all breast cancers are triple-negative, which lack the three receptors—estrogen, progesterone or HER2—that would make them responsive to targeted therapies, explained researchers from the Garvan Institute of Medical Research in Sydney, Australia. Overall, they said, these patients have a higher risk for disease recurrence and shorter survival than those with other breast cancer types, but they tend to fall into two categories:

  1. Those who succumb to their disease within three to five years, regardless of treatment; and
  2. Those who remain disease free for longer than the average non–triple-negative breast cancer patient (at least eight years post-diagnosis).

The Sydney-based research team found a gene known as inhibitor of differentiation 4 (ID4) that drives the aggressive form of the disease (Nat Commun 2015;6:6548, PMID:25813983). The aggressive form of triple-negative breast cancer appears to arise from stem cells, whereas the more benign form appears to arise from specialized cells, they explained.

Stem cells have many of the same features as malignant cells. They are plastic and flexible, and can proliferate and spread into other tissues. Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear, but apparently, ID4 determines whether a stem cell remains a stem cell or whether it differentiates into a specialist cell. Notably, when the high levels of ID4 in a stem cell are switched off, other genes that drive cell specialization are switched on.

Alex Swarbrick, PhD, and Simon Junankar, PhD, researchers at the Garvan Institute spearheaded this large interdisciplinary study, which links the development of the mammary gland in mice with human breast cancer. They found that ID4 not only marks, but also appears to control, the highly aggressive form of triple-negative breast cancer.

“We found that ID4 is produced at high levels in roughly half of all triple-negative breast cancers, and that these cancers have a particularly poor prognosis,” Dr. Swarbrick said. “We also showed that if you block the ID4 gene in experimental models of triple negative breast cancer, the tumor cells stop dividing.”

Blocking ID4 switches on the estrogen receptor 3 and several other genes expressed by the best-prognosis breast cancer, which could improve the therapeutic prospects for these patients, he explained. “Estrogen receptor–positive breast cancers have a relatively good prognosis because the drug tamoxifen is effective at blocking the estrogen receptor and hence their growth,” Dr. Swarbrick said.

“We speculate, therefore, that by blocking ID4 it might be possible to turn stem cell–like breast cancers into less aggressive breast cancers that may even respond to tamoxifen. If we are correct, that would be remarkable.”

The next step for the team will be to study the biochemistry of ID4 in a cell to determine how best to block it and switch it off in individuals. There are also plans to undertake therapeutic experiments mouse models to test whether switching off ID4 sensitizes a tumor to tamoxifen.

“We don’t know yet whether we are seeing a real estrogen-dependent cancer after ID4 is blocked—one with an effective estrogen receptor—or just a caricature of one,” he said.

Source:  Clinical Oncology News