Discovery of a cell mechanism that reduces effectiveness of breast cancer treatment

Researchers from Massachusetts General Hospital, Harvard Medical School and CIC bioGUNE discover a complex cell mechanism activated by a protein —HOXB9— that becomes an obstacle for radiation effectiveness.

Scientists all over the world continue to focus their research on breast cancer. As a consequence, knowledge of the behaviour of tumour cells is growing, as well as of their interactions with the microenvironment. There are, however, many questions still unanswered.

A new collaborative study carried out by the laboratory of Dr María Vivanco, researcher at the Cell Biology and Stem Cells Unit in the Center for Cooperative Research in Biosciences, CIC bioGUNE, and the groups led by Dr Zou and Dr Maheswaran in Boston, has provided insight into one of these mysteries: a cell mechanism that explains how a protein - called HOXB9 - helps cancer cells to avoid the attack of treatments such as radiation, and prevents the therapy from having the desired effect on certain types of breast cancer.

The study was recently published in Proceedings of the National Academy of Sciences (PNAS). The study shows that cells that express higher levels of the HOXB9 transcription factor are more likely to survive the radiation used as breast cancer treatment.

A complex mechanism induced by this protein has been discovered, which manages to activate a whole chain of cell processes in which different proteins - such as ATM kinase, amongst others - intervene, and which make certain cancerous cells more resistant to treatment. Dr Vivanco explains, "when the tumour is exposed to radiation it induces DNA damage – a phenomenon that results in formation of double-stranded DNA breaks - leading the cells to respond and try to repair the damage caused in the DNA using another mechanism - called the DNA damage response," by activating ATM kinase. In this way, the cell cycle is stopped and the DNA is repaired in order to maintain chromosome stability.

HOXB9 expression causes an increase in survival of cells that have been exposed to radiation. This higher resistance occurs because of the acceleration of response to radiation and its higher recovery capacity after DNA damage. On the other hand, reduction of the levels of this protein, leads to increased cell sensitivity to radiation. Furthermore, the growth factor TGFbeta (a HOXB9 target) is also involved. Therefore, HOXB9 facilitates DNA repair by activation of the TGFbeta signalling pathway, which elevates ATM phosphorylation, accelerates DNA damage response and radiation resistance.

The published research is the continuation of another study carried out last year by CIC bioGUNE, Massachusetts General Hospital and Harvard Medical School, which showed that this same protein (HOXB9) is overexpressed in breast cancer and that its expression levels are associated with high tumour grade.