The Story of ESR1

How observing sheep led to a breast cancer drug.

While soaping up in the shower, a woman feels a small lump in her left breast. The next day, a mammogram reveals a suspicious white mass enmeshed in surrounding healthy tissue. After an ultrasound scan rules out a cyst and a more detailed mammogram and a magnetic resonance image (MRI) confirm presence of a growth, the woman has a biopsy. Cancer cells in the sampled and stained tissue are sprinkled with brown dots, like freckles – these are estrogen receptors. The patient’s cancer is “ER-positive.”

Estrogen receptors are proteins that bind to molecules of the steroid hormone estrogen inside cells. Two genes (ESR1 and ESR2) encode two different estrogen receptors, which interact (see right). The ESR1 receptor is a single amino acid chain, but it folds into a dozen helices radiating from a core, resembling the snakes spiraling from the head of the Greek monster Medusa. In the process, they contort into shapes that attract yet other proteins, which determine whether the receptors turn certain genes off or on.

Which genes the estrogen receptor and its piggybacked estrogen turn on and off determine the effects of the hormone. In a cancer, the altered pattern of gene activation and repression feeds the tumor’s growth. Cancer begins in epithelial (lining) cells in the breast that are abnormal in that they have many more estrogen receptors than do surrounding healthy cells. When the abundant receptors bind to estrogen, the cycle of cell division accelerates, and the cells form a tumor.

Understanding the tango between the estrogen receptor and its cargo led to discovery and development of tamoxifen (marketed as Nolvadex and Soltamox), a drug that prevents and treats breast cancer. Since then, we have discovered better ways to interfere with this engine that drives cancer cells. We can interfere with the estrogen receptor by “blocking” it, either by binding to it in place of estrogen, as tamoxifen does, or by interfering with how the receptor transmits its signal to other parts of the cell.

Tamoxifen was the first selective estrogen receptor response modulator, or SERM, to come on the market. In many of the 80 percent of breast cancers that are ER-positive, the drug is slightly altered in the body, becoming able to bind receptors 30 to 100 times stronger than estrogen does. With the drug blocking receptors, the hormone can’t bind to them and the cells never get the signal to divide. Tamoxifen has extended or saved millions of lives since it came on the market 35 years ago. In fact, it is the most successful personalized therapy to date. But it started out as a failed contraceptive.

The story of tamoxifen took many twists and turns. It began in 1876, when a medical student seeking the quiet of the Scottish countryside to write his thesis had an epiphany while watching lambs being weaned on a neighboring sheep farm. “It was clear to me that the changes that take place in the mammary gland in the process of lactation are almost identical … with what takes place in a cancerous mamma,” Sir George Beatson, M.D., would write two decades later in the medical journal The Lancet. He also noted that removing cows’ ovaries, or keeping the bovines perpetually pregnant, kept the milk flowing. Ovaries were somehow connected to rapid cell division. The link: estrogen.

Beatson went on to an illustrious career, working with Joseph Lister, the father of antiseptic surgery. (Yes, Listerine was named for him.) In 1895, Beatson saw a patient whose breast tumors had grown back after surgery, spreading over her chest. Desperate, the 33-year-old mother of two agreed to participate in the experiment that the doctor had been thinking about since his time on the Scottish farm. So on June 15 of that year, he removed her fallopian tubes and ovaries. By mid-July, her tumors began to shrink; by October, they were gone.

Removing ovaries, which stops the estrogen supply, was done until 1960 to treat breast cancer. But it only worked on a third of patients – likely those with ER-positive cancers. In the early 1960s, estrogen was thought to interact with enzymes. Then Elwood Jensen, an organic chemist at the University of Chicago, found that it didn’t work that way. He tagged estrogen with radioactive hydrogen and gave it to female rats. The hormone lit up in the vagina and uterus, indicating that it bound something there – a receptor. In 1968 Jensen developed a test to detect the estrogen receptor on human breast cancer cells.

Receptors are the chemical catchers’ mitts that enable drugs to act on or enter cells. They are the backbone of the pharmaceutical industry. But the journey of drug development often takes wrong turns. That’s what happened with tamoxifen. It was first synthesized at Merrell Laboratories in Cincinnati, given the name MER25, and pursued to lower cholesterol. But because the structure resembled that of estrogen, researchers thought it might also work as a late-acting contraceptive, a morning-after pill, by blocking estrogen receptors. Alas MER25’s life as a possible drug was discontinued due to side effects that were eventually ruled out.

But it would be discovered again. Tamoxifen resurfaced at Imperial Clinical Industries Pharmaceuticals in England (today AstraZeneca) in 1962. Reproductive endocrinologist Dora Richardson synthesized it, and what is now tamoxifen was named ICI46,474. When her colleague Arthur Walpole found that ICI46,474 had inconsistent effects on mice and rats, the project stalled again – until another young researcher became intrigued.

In 1969, Vernon Craig Jordan was a Ph.D. student in pharmacology at the University of Leeds. Since boyhood he’d wanted “to develop drugs to be able to treat cancer. Everybody thought it was just a crazy idea,” he wrote years later. He thought an estrogen-like molecule that would bind to the estrogen receptor might intercept the signal to divide, working like a dummy key in a lock. But others deemed the approach a “dead end,” and when the young man sought a new mentor, Dr. Walpole stepped in and convinced ICI to support Jordan’s research.

Times were changing. At the very end of 1971, U.S. president Richard Nixon had declared a “war on cancer” and cancer research became a society-wide priority. But academia remained old-fashioned, and a mentor from a business rather than a university was frowned upon during this period before modern biotechnology. Jordan showed that tamoxifen indeed blocked the estrogen receptor. Although an initial small clinical trial for breast cancer had lackluster results, a second study using a higher dose was more promising.

(The failed contraceptive turned anti-cancer agent wouldn’t be the first repurposed drug. Many years later, an angina drug with unexpected side effects would spawn the erectile dysfunction drug sildenafil, marketed as Viagra.)

By 1980, clinical trials including only ER-positive patients demonstrated clearly that tamoxifen extended life for women who had early or metastatic breast cancer and had already had standard chemotherapy. In the 1990s, 13,800 healthy women who had strong family histories of breast cancer, both pre- and post-menopausal, took tamoxifen for years to see if it prevented cancer – and it did, lowering risk by 50 percent. However, in younger women tamoxifen may cause symptoms of menopause, and may raise the risk of developing certain cancers.

The drug that was nearly discarded became the first targeted therapy for breast cancer as well as the first chemopreventive agent. Dr. Jordan became the unofficial father of tamoxifen. “A series of chance events turned ICI46,474 from a lab curiosity into a pioneering medicine over the next 20 years,” he wrote. The good news continues. A study published in December 2014 showed that tamoxifen safely prevents cancer recurrence for 20 years.

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