Paclitaxel May Drive Breast Cancer Metastasis

Paclitaxel chemotherapy may turn on a stress gene that allows cancer cells to escape from the primary tumor.

Chemotherapy is a common treatment for nearly all cancers, including breast cancer; however, findings from a new study published by the Proceedings of the National Academy of Sciences suggest that treatment with paclitaxel chemotherapy may also help breast cancer cells metastasize to the lungs.

The study authors explored the events that lead to metastatic cancer from chemotherapy in hopes that they could inhibit metastasis, while preserving the benefits of the drugs.

Paclitaxel induces numerous molecular changes that allow breast cancer cells to escape. Unfortunately, the drug also makes the lungs ideal for cancer cells, facilitating metastasis in mice models, according to the study.

The authors then analyzed data from women with the disease and noted that the animal findings may be applicable to humans as well.

“That chemotherapy can paradoxically promote cancer progression is an emerging revelation in cancer research. However, a molecular-level understanding of this devastating effect is not clear,” said senior study author Tsonwin Hai, PhD.

The alterations in the tumor and the lungs are contingent on the Atf3 gene, which is turned on by stress, according to the study. When examining human data, the authors found increased Atf3 expression among patients who received chemotherapy compared with those who did not.

“This gene seems to do 2 things at once: essentially help distribute the ‘seeds’ (cancer cells) and fertilize the ‘soil’ (the lung),” Dr Hai said.

The authors report that paclitaxel seems to send signals to increase the number of molecular doors that allow cancer cells to escape into the blood and metastasize, according to the study.

“I think it’s an active process—a biological change in which the cancer cells are beckoned to escape into the blood—rather than a passive process in which the cancer cells get into the bloodstream because of leaky vessels,” Dr Hai said.

The authors also found that paclitaxel makes the lungs an ideal ground in which circulating breast cancer cells can implant.

“There are signals that help cancer cells enter the lungs and set up shop, that make the environment more immunologically tolerant to cancer cells,” Dr Hai said.

An early molecular-level understanding of how chemotherapy can increase the risk of metastasis is underway, according to the authors.

The cancer cells assessed in the mouse models were very aggressive. Further studies should aim to determine if paclitaxel can increase the risk of cancer cell metastasis in earlier stage disease, the authors noted.

While their findings were significant, much more work must be done before the findings can be extrapolated to humans, according to the study.

“At this point, what our study and the recent literature on chemotherapy taught us is that it is prudent to keep our mind open, realizing that chemo can help treat cancer, but at the same time may increase the possibility of the spread of that cancer,” Dr Hai said.

The most promising finding from the study is that paclitaxel turns on the stress gene Atf3. This will be the focus of further studies, according to the study.

“It’s possible there could be a treatment given in conjunction with the chemo that would inhibit this problem by dampening the effect of the stress gene Atf3,” Dr Hai concluded.