Hormonal Therapy Unveiled: Exploring its Role in Fighting Breast Cancer

Work carried out by analysts from the Integrated Cancer Genomics Laboratory at the Advanced Centre for Training, Research, and Education in Cancer (ACTREC) in Mumbai’s Tata Memorial Centre has revealed more insight into the molecular mechanism through which progesterone therapy before breast cancer surgery is very liable to increase the survival rates of patients.

A group led by Dr. Amit Dutt at the ACTREC found through in vitro examinations that when breast cancer cell lines were treated with progesterone, two genes SGK1 and NDRG1 were created in excess amounts (overexpressed). They also observed that the expression of a few microRNAs was reduced (down-regulated) in light of the hormone treatment. Two specific microRNAs that were downregulated were found to also manage the expression of the SGK1 gene.

Increased survival rate

Since the typical capability of the two microRNAs is to reduce the amount of SGK1 enzyme delivered, when the level of microRNAs drops, the amount of SGK1 enzyme produced increases. Through the activity of SGK1 and two other genes, and the two microRNAs, the ability of the breast cancer cells to migrate and invade is decreased, subsequently increasing the survival rates of patients going through hormone treatment before surgery.

In a recently published study in the journal, Breast Cancer Research, the group led by Neelima Yadav in Dr. Dutt's lab extended the scope of their past work to focus on the role of non-coding genes; non-coding genes do not produce any proteins but for control the expression of other genes. The work was to reveal the molecular mechanism of any non-coding gene in giving the therapeutic benefit of progesterone on breast cancer cells.

The study discovered that therapy of breast cancer cells with progesterone brings about a down-regulation of a long non-coding linc RNA known as the Down Syndrome Cell Adhesion Molecule (DSCAM-AS1).

"Likewise with progesterone treatment, we found that with silencing of DSCAM-AS1 expression, the ability of breast cancer cells to invade and migrate is slowed down," Ms. Yadav says.

In breast cancer patients, the amount of DSCAM-AS1 present is raised. The group also found that DSCAM-AS1 acts like a sponge and drains the accessibility of another non-coding microRNA called the miR-130a. Also, the level of estrogen receptors in breast cancer cells is increased, which serves as an indicator to start hormonal treatment.

Elevated level of microRNA

But when progesterone is given remotely, the amount of DSCAM-AS1 that is available reduces, and consequently the sponging effect of DSCAM-AS1 also sees a dip. This outcome raised levels of the microRNA (miR-130a) that are freely available. As the level of the microRNA increases, there is a greater amount of them binding to the estrogen receptor. "The review tossed a surprise. We found that miR-130a is known to regulate the level of estrogen receptors in breast cancer cells," says Dr. Dutt.

Dr. Dutt says the identification of DSCAM-1in blood or tumor tissue can almost certainly give data about the aggressiveness of breast cancer and prognosis. "Non-coding RNA-based diagnostic and screening techniques are still in the beginning phases of development. We need t further validation before using it in clinical practice," he says.

"Our review recognizes a three-tiered regulatory network wherein DSCAM-AS1 sponges off miR-130a to downregulate estrogen receptor expression in response to progesterone. We show that an increased expression of miR-130a or decreased expression of DSCAM-AS1 relates with further improved survival outcomes in breast cancer patients, like the effects of progesterone treatment," says Dr. Dutt. "When taken in general, our research addresses the most first step in portraying the progesterone-responsive long non-coding RNAs and their mechanistic functional insight downstream of progesterone in breast cancer cells, lined up with other regulatory pathways."

"The potential therapeutic advantage of progesterone and its mediators is the highlight of the ongoing study," he says.

Hormone treatment targets hormone receptors in breast cancer cells to slow or stop the development of cancer. It is a standard therapy for breast cancer and is in many cases used in combination with different therapies like surgery, radiation, and chemotherapy. In any case, protection from hormone treatment in breast cancer is a huge issue in treating hormone receptor-positive breast cancer.

One of the primary systems of resistance from hormone treatment is the presence of mutations in the hormone receptors themselves or through the down-regulation of its expression levels.

One more implication of the most recent study is that when the microRNA miR-130a binds to the estrogen receptors, it could lead to cancer cells becoming resistant to hormone treatment.

"It is at present a theory and must be confirmed through additional examinations," says Dr. Dutt.