In the last three decades, thousands of women with breast cancer have taken the drug tamoxifen（三苯氧胺） , only to discover that the therapy doesn't work, either because their tumors do not respond to the treatment at all, or because they develop resistance to it over time. Now researchers at the University of California, San Francisco (UCSF) have discovered the molecular² basis for tamoxifen resistance and found a potential way to defeat it. On Nov. 13, 2011, at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, UCSF oncologist Pamela Munster, MD, and her colleagues presented the results of clinical studies and laboratory experiments that show how some tumors resist tamoxifen and how this resistance can be overcome by administering a second class of drugs.

"Understanding the mechanism³ of tamoxifen resistance and how to defeat it may help a large number of women with hormone-resistant breast cancer," said Munster. "It may lead quickly to new, more effective treatment strategies and may help to identify biomarkers to help to gauge⁴（测量） whether or not someone will respond to treatment in the first place."

Tamoxifen Resistance and Breast Cancer The National Cancer Institute estimates that more than 200,000 Americans are diagnosed with breast cancer every year. It is the second leading cause of cancer death among American women, claiming more than 40,000 lives in 2009 alone.

About 65 percent of women with breast cancer have tumors that, when examined in biopsies, show signs of co-opting a naturally occurring molecule⁵ in the human body called the estrogen receptor. This receptor helps to stimulate⁶ the proliferation and growth of cells -- something that is normally tightly controlled in the body.

Tumors can use the machinery⁷ of this receptor to stimulate the unregulated growth and proliferation of cancer cells. Doctors have known for decades that this is one of the main drivers of breast cancer, and elevated levels of estrogen receptor is something oncologists look for when they take tumor¹ biopsies.

Tamoxifen, which blocks the estrogen receptor, is the front-line treatment for premenopausal women whose breast cancer biopsies show elevated levels of the receptor. It can be something of a wonder drug when it works, inhibiting⁸ cancer growth and shrinking tumors without the same side effects as chemotherapy.

However, tamoxifen only works in half the women to whom it is prescribed. It may not work in some women because they may have forms of cancer in which the estrogen（雌性激素） receptor does not actually play a central role. However, many women taking tamoxifen acquire resistance to it. Their tumors respond to the treatment at first, but then the cancer rebounds⁹ and develops the ability to proliferate¹⁰ and grow even when the estrogen receptor is blocked.

While doctors have documented cases of tamoxifen resistance in the clinic for decades, nobody knew exactly how the cells were able to acquire resistance. Many scientists thought that genetics were to blame -- certain variations in one's DNA¹¹ that would pass from parents to children and make one more likely to develop a tamoxifen-resistant form of breast cancer. According to Munster, that is not the case.

"We always thought that resistance was genetic," said Munster. "But now we have discovered that cells have a way of developing resistance by means of epigenetic（后生的） modification¹²."