Uncovering the Role of Progesterone in the Treatment of Breast Cancer

Clinicians have long observed that breast cancer patients who are both estrogen receptor (ER) positive and progesterone receptor (PR) positive have better clinical outcomes. These patients tend to respond better to treatment and have a lower risk of relapse, even though they are treated with the same hormone therapy as their ER-positive, PR-negative counterparts.

Now, researchers from the United Kingdom and Australia have uncovered the molecular underpinnings of why upregulation of both hormone receptors results in better tumor control. Their results, published in Nature, suggest that hormone therapy with progesterone could be used in the treatment of ER-positive, PR-positive disease, which makes up about half of all diagnosed breast cancers.

Using ER-positive, PR-positive cell-line xenografts, as well as primary ER-positive breast tumor cells excised from patients and grown in a lab, Jason S. Carroll, PhD, of the Cancer Research UK Cambridge Institute, and colleagues observed that the receptors for estrogen and progesterone physically interacted within the cell. They also found that the global gene expression profile of these cells was different when the cells were exposed to estrogen alone vs estrogen plus progesterone and, in the presence of both hormones, was linked to better clinical outcomes.

Adding progesterone to tamoxifen, the researchers found that the ER is redirected to different transcriptional targets, and its activity is blocked, said Jacqueline F. Bromberg, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, who was not involved in the study.

Moreover, the use of progesterone with tamoxifen slowed tumor growth compared with either hormone alone in both cells grown in the lab and in breast cancer tumors implanted into mice.

“[This study] beautifully elucidates a previously unknown function for the PR in modulating the behavior of the ER in breast cancer,” said Bromberg.

While important, the preclinical study cannot yet be directly translated into clinical trials, said Bromberg. All of the experiments in mouse and human models required the addition of estrogen, as well as tamoxifen and progesterone, which is not clinically relevant. Additionally, the type of progesterone used in the study is not one used in clinical practice.