Anti-oestrogenic therapies can suppress the growth of cancer that does not express oestrogen receptors; when combined with immune checkpoint inhibitor therapies, they halt tumour progression in mice models.

Oestrogen, a group of female hormones, is known to be involved in cancer progression, especially breast cancer. About 75 % of breast cancers are oestrogen-sensitive: they express the hormone receptor oestrogen receptor α (ERα), and oestrogen promotes tumour growth. Surprisingly, oestrogen has been observed to promote tumour growth in ERα-negative cancers, such as triple-negative breast cancer (TNBC), for reasons that are not fully understood.

A team of researchers from the Institute for Genetic Medicine (IGM) at Hokkaido University has uncovered how oestrogen affects the tumour microenvironment and promotes tumour growth in ERα-negative cancers. Their findings were published in the British Journal of Cancer.

“Generally speaking, oestrogen directly affects cancer cells to promote cell survival and proliferation, and this has been considered to hold true only for oestrogen-sensitive cancers,” explains Nabeel Kajihara, lead author of the paper. “Oestrogen is also documented to play other roles in the tumour microenvironment, effectively suppressing the immune response and protecting tumours.”

The researchers analysed patient data from The Cancer Genome Atlas (TCGA) and conducted experiments in cell cultures and mice models to understand what was happening.

From the TCGA data, they observed that, in TNBC, oestrogen suppresses the induction of cytotoxic T cells, which typically recognise and destroy cancer cells. They confirmed this observation in mice TNBC and colon cancer models, which do not have oestrogen sensitivity; they then went one step further and studied the effects of anti-oestrogenic therapy on these cancers in mice models. Therapy with fulvestrant, the most effective oestrogen signal blocker currently approved for clinical use, suppressed the growth of tumour cells. Tumour growth was also suppressed by two other approved anti-oestrogenic drugs, tamoxifen and anastrozole, confirming that oestrogen signal-blocking was responsible.

Oestrogen signal blockers modulate immune response to increase the production of cytotoxic T cells, specifically by preventing the activity of oestrogen. The team also showed that therapy combining oestrogen signal blockers with a class of drugs called immune checkpoint inhibitors (ICIs) drastically suppresses tumour progression in mice models. Most notably, the combination of fulvestrant (anti-oestrogenic) and anti-CTLA-4 (ICI) resulted in the complete suppression of TNBC tumour progression.

“We have demonstrated that anti-oestrogenic therapies can potentially maximise therapeutic efficacy of cancer immunotherapy regardless of tumour cells’ ERα expression,” concludes Professor Seino. “However, this is only the first step; future clinical research is required to develop cancer therapies that utilise this approach.”

Source: Hokkaido University