A 'previously overlooked' variant of a common protein may hold the key to augmenting the effectiveness of breast cancer treatment, according to a new study from the University of Manchester.
A variant of the RAC1 protein, which is present in nearly all human cells, is crucial for tumour formation and for response to cancer stem cell treatments, according to a new study published in the cancer journal Oncogene. Targeting the variant, known as RAC1B, "could be a potential way of improving treatment for breast cancer", they said.
RAC1 plays a vital role in maintaining the health of all organs, so directing cancer treatment against it has rarely been a research focus, even though it has been implicated in therapy resistance of tumour cells against both cytoablative and targeted treatments.
However the uncommon RAC1B, the only known alternatively spliced variant of the small GTPase RAC1, is particularly important in cancer and has previously been shown to be an important mediator of colorectal tumourigenesis.
The new research study, led by Dr Ahmet Ucar, Breast Cancer Now research fellow in the Division of Cancer Sciences at the University of Manchester, found that breast cancer stem cells (BCSC), also known as tumour-initiating cells, which are believed to underlie cancer’s resistance to treatment, recurrence and metastasis, also rely on RAC1B.
Variant Protein 'Essential' for Tumour Formation
Unlike RAC1, RAC1B function is dispensable for normal mammary gland development and mammary epithelial stem cell activity, the authors said. But loss of RAC1B function in a mouse model of breast cancer hampered BCSC activity, and increased the cells’ chemosensitivity to doxorubicin treatment.
The researchers studied the human breast cancer cell line MCF7, and demonstrated that RAC1B function was essential in BCSCs for their plasticity, chemoresistance to doxorubicin treatment and tumour-initiating abilities.
Using genetically engineered mouse models, they showed that in HER2/Neu-driven mammary tumours, RAC1B was expressed by a substantial subset of BCSCs, which required RAC1B function for their sustension and activity. Furthermore, when the team transplanted breast cancer cells into the mice, they found that the cancer cells lacking RAC1B formed no visible tumours, even after 100 days.
The loss-of RAC1B function sensitised the cells to the chemotherapeutic effect of doxorubicin treatment in the laboratory, so that breast cancer cells grown without RAC1B didn't recover after being treated with doxorubicin, whereas those cancer cells that retained RAC1B "made a quick and robust return when the treatment was stopped". In addition, the cancer cells with higher levels of RAC1B recovered faster.
The Cancer Genome Atlas (TCGA) dataset analysis revealed that higher RAC1B expression levels in breast tumours predicted worse overall survival in doxorubicin-treated patient groups, "thus providing clinical confirmation to our findings in the experimental models of breast cancer", the team said.
'Attractive Target' for Future Treatment
This is the first time that targeting RAC1B has been identified as a potential way to improve breast cancer treatment. "As the absence of RAC1B doesn’t cause any harmful effects to organs, it makes it an attractive target for future breast cancer treatments," the researchers said.
However, development of BCSC-targeting therapies has been held back by their heterogeneity and the lack of BCSC-selective molecular targets. "Our data suggest that RAC1B is a clinically relevant molecular target for the development of BCSC-targeting therapies that may improve the effectiveness of doxorubicin-mediated chemotherapy," the authors concluded. "Taken together, our results propose RAC1B as a promising BCSC-specific molecular target to sensitize the RAC1B-expressing chemoresistant breast tumours to the therapeutic effects of doxorubicin treatment."
Two Decades of Research
Dr Ucar said: "Developing cancer stem cell treatments to target tumours at their root has been a research aim for more than 20 years, but until now has proven elusive."
The concept has been hard to confirm in breast cancer due to high levels of heterogeneity within the BCSC pool, and the lack of appropriate molecular targets showing tumour-specific stem cell selectivity for their functional indispensability.
Thanks to the new study, "for the first time, our research has shown that without RAC1B, breast cancer stem cells can't form tumours and become more vulnerable to chemotherapy, making the treatment even more effective", Dr Ucar said. "Positively, RAC1B isn't needed for healthy cells, so targeting RAC1B with new cancer treatments is unlikely to have severe side effects.
"We hope that further research will help translate these findings into targeted therapies for breast cancer patients."
Dr Simon Vincent, director of research, support and influencing at Breast Cancer Now, which funded the study, commented: "It’s exciting that a variant of a previously overlooked common protein could hold the key to transforming the way we treat breast cancer. Early-stage discoveries like this can help provide the building blocks for the breakthroughs of the future, leading to new and effective treatments for the 55,000 women and 370 men who are diagnosed with breast cancer in the UK every year."
