Novel mode of action of naturally occurring hormone, Progesterone, in suppressing breast cancer
11 Sep 2017
By Dr Amit Dutt, Intermediate Fellow
A randomized clinical study carried out at the Tata Memorial Center in 2011 revealed that mimicking “luteal phase of menstrual cycle” by artificially elevating the levels of progesterone in patients at the time of primary breast cancer surgery was found to be beneficial in terms of survival among those breast cancer patients whose tumor had spread to the nearby lymphatic nodes (1). This landmark finding that has changed clinical practice though was counter intuitive, based on the understanding of progesterone biology, as the effect of progesterone was observed even among patients whose tumor cells did not express the receptor for progesterone on their surface. This clinical observation raised an important biological question - how do breast cells that do not produce progesterone receptor and those that do, respond to external progesterone treatment in a uniform manner?
In a set of two parallel research publications from our laboratory, we provide some interesting leads to help us understand the biological complexity underlying this disease. We show that breast cancer cells treated with naturally occurring progesterone induces deactivation of protein kinases (specifically EGFR, AKT and ERK1/2) and delay in the invasion and migration ability of these breast cancer cells in a cell culture setting (in vitro). Interestingly, this phenomenon was observed independent of the availability of progesterone receptors on the cells (2).
Our analysis also leads to a surprising discovery of a novel feedback mechanism that regulates the presence of progesterone receptor in the breast cancer cells following progesterone treatment. We show that progesterone treatment of breast cancer cells lead to an increase in a novel miRNA miR-129-2 that effectively brings down the levels of progesterone receptor, as an early response (3). miRNAs are small RNA molecules in the cell responsible for regulating expression of various genes. We further demonstrate that blocking the function of miR-129-2, restores the availability of progesterone receptor in these breast cancer cells. Consistent with this finding, TCGA (The Cancer Genome Atlas) analysis of 359 primary breast cancer tumors revealed an increased expression of miR-129-2 in progesterone receptor-negative patients compared to progesterone receptor-positive ones.
Taken together, we present the first leads to model a successful randomized clinical study in vitro to systematically elucidate the role of protein kinases that potentially underlie the clinical outcome of pre-operative progesterone intervention in breast cancer. Furthermore, our study suggests that inhibition of miR-129-2 restores progesterone receptor in breast cancer cells, and hence could potentially be helpful for patients with inadequate progesterone receptor expression levels under adjuvant or neo-adjuvant settings along with hormonal therapy in breast cancer.
1. Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. Badwe R, Hawaldar R, Parmar V, Nadkarni M, Shet T, Desai S, Gupta S, Jalali R, Vanmali V, Dikshit R, Mittra I. J Clin Oncol. 2011 Jul 20;29(21):2845-51. doi: 10.1200/JCO.2010.33.0738. Epub 2011 Jun 13.
2. Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status. Godbole M, Sharma K, Badwe R, Gupta S, Dutt A. Cellular Oncology. 2017
3. miR-129-2 mediates down-regulation of progesterone receptor in response to progesterone in breast cancer cells. Godbole M, Chandrani P, Gardi N, Dhamne H, Patel K, Yadav N, Gupta S, Badwe R, Dutt A. Cancer Biology & Therapy. 2017
Banner image credit: Dr Amit Dutt. Breast cancer-derived cell stained with crystal violet dye