TMC team overcomes resistance to hormonal therapy for breast cancer

Amit Dutt-Optimized
In in vitro studies, the anti-microRNA was found to be very effective in keeping the expression of progesterone receptor intact, says Dr. Amit Dutt (centre)

The molecular mechanism of hormonal therapy’s protective benefits in breast cancer patients identified.

Researchers at the Tata Memorial Centre (TMC), Mumbai have found a possible reason why certain breast cancer patients become resistant to hormonal treatment. And the good news is that they have designed an anti-microRNA (small non-coding RNA) which can probably help in overcoming the resistance to hormonal therapy.

In another study, the researchers have found the molecular mechanism that is responsible for conferring protective benefits of progesterone hormone in breast cancer patients. Progesterone hormone treatment prior to breast cancer surgery reduces recurrences and increases survival in node positive cases, a 2011 clinical trial carried out by Dr. Rajendra Badwe and colleagues at the Tata Memorial Centre (TMC) found.

Role of microRNA

A team led by Dr. Amit Dutt from the Integrated Cancer Genomics Laboratory, ACTREC at TMC has found that following progesterone treatment, the expression of progesterone receptor in the breast cancer cells is turned down or reduced. Turning down the expression of progesterone receptor was through the action of small RNA molecules (microRNA). MicroRNAs are known to have regulatory functions inside the cells.

The researchers took breast cancer cells and treated them with progesterone and performed deep-sequencing using next generation sequencers for small RNA molecules. “We found three microRNAs to be consistently over-expressed [produced in abundance] in response to progesterone treatment. And the over-expressed microRNAs turn down the expression of the progesterone receptor. The over expression of microRNAs was independent of the progesterone receptor status of the breast cancer cells,” says Mukul Godbole from the Integrated Cancer Genomics Laboratory, ACTREC at TMC and the first author of both the papers.

Using biochemical approaches, the researchers were able to validate one (miR-129-2) of the three microRNAs that is over-expressed. The results were published in the journal Cancer Biology & Therapy.

To confirm their results, the researchers analysed the expression of the particular microRNA (miR-129-2) in The Cancer Genome Atlas (TCGA). They found that patients with high levels of miR-129-2 microRNA had “significantly lower expression” of progesterone receptor compared with patients with no expression of this microRNA.

Overcoming hormonal therapy resistance

It is common to see patients undergoing hormonal treatment becoming resistant to the treatment. “Now we know a possible reason why patients become resistant to hormonal therapy,” Dr. Dutt says. Dr. Dutt is an Intermediate Fellow of the Wellcome Trust DBT India Alliance.

And the good news is that in adjuvant setting after surgery it is possible to prevent the microRNAs from turning down the expression of the progesterone receptor. By using an anti-microRNA that the team designed it is possible to reduce the level of microRNAs. The anti-microRNA ensures that the expression of progesterone receptor remains intact and patients respond to progesterone hormone treatment.

“In in vitro studies, the anti-microRNA was found to be very effective,” says Dr. Dutt. By using the anti-microRNA, it might be possible to turn the clock back in the case of patients who have developed resistance to hormonal therapy.

Understanding the molecular mechanism

In another study, the researchers have found the molecular mechanism that is responsible for conferring protective benefits of progesterone hormone in breast cancer patients. A clinical trial at TMC found progesterone hormone treatment prior to breast cancer surgery reduces recurrences and increases survival in node positive cases.

Specifically, they found that both breast cells which produce progesterone receptor and those which do not produce progesterone receptor respond uniformly to external progesterone treatment.

The researchers found that irrespective of the progesterone receptor status of breast cancer cells, progesterone hormone treatment inactivates a set of 12 protein kinases (which are required for basic functioning of a cell).

The inactivation of the 12 kinases results in the inhibition of breast cancer cell migration and invasion. As a result, there is a delay or reduced chances of cancer cells spreading (metastasis), which is a major cause of recurrence in breast cancer patients. The results were published in the journal Cellular Oncology.

“This finding is very important as it gives us an in vitro model to understand the intricacies of progesterone and the inhibition of invasion,” says Dr. Dutt.

“Besides understanding the molecular mechanism of progesterone hormone treatment, the real implication of the study will be that we may be able to select patients who will benefit from progesterone treatment,” says Sudeep Gupta from the Department of Medical Oncology at TMC and one of the authors of the two papers.

Published in The Hindu on September 16, 2017

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