Discovery sheds light on how breast cancer cells progress to more aggressive forms

August 07, 2002

HOUSTON - Despite recent advances in breast cancer treatment that have led to long-term survival for millions of women, most tumors eventually stop responding to standard therapies. The result is a poor prognosis for the patient and frustration for doctors who must turn to investigational therapies in hope of slowing the progression of the disease.

But now researchers at The University of Texas M. D. Anderson Cancer Center have begun to understand how breast cancer cells suddenly stop responding to treatment and become more aggressive. The finding, which appears in the Aug. 8 issue of the journal Nature, points to a potential target that in principle, may reverse the process and restore hormone responsiveness to breast cancer cells.

A research team led by Dr. Rakesh Kumar, professor of cellular and molecular oncology, reports discovering a new form of a protein that is associated with aggressive forms of cancer, including breast cancer. The new protein, termed MTA1s (metastatic tumor antigen 1, short version), appears to intercept the key protein receptor that is responsible for communicating with the female hormone estrogen inside cells.

An estimated 192,200 women will be diagnosed with invasive breast cancer and 40,200 women will die this year, according to the American Cancer Society. About 60 percent of breast cancers are classified as estrogen-receptor positive by conventional evaluation methods, meaning that they respond to signals from the female hormone estrogen through its receptor. These patients typically respond well to hormonal treatment with tamoxifen and other anti-estrogenic compounds, which block estrogen signals that tell the cancer cells to multiply.

But after a period of time, some breast cancer cells suddenly become hormone independent, growing and multiplying more rapidly, even in the presence of anti-estrogen treatment. Physicians typically determine hormone responsiveness by looking for the estrogen receptor molecule in the cell's nucleus - the command center of the cell and the place where estrogen receptors normally reside. When estrogen receptors can no longer be found in the nucleus, the cancer cell is termed "hormone independent" and other types of therapy must be tried.

"The underlying molecular mechanisms for aggressive tumor behavior and estrogen-receptor negative tumors are poorly understood, and this is an area of intense research," Dr. Kumar says. "This research is an important step toward understanding how breast cancers become hormone independent. With greater understanding, we can design new therapies to prevent or perhaps reverse this transformation."

Dr. Kumar and his colleagues discovered the new protein while studying MTA1. The protein is known to contribute to the transformation of breast cancer tumors to more aggressive forms. They discovered that MTA1s is a naturally occurring short form of MTA1, but while MTA1 interacts with the estrogen receptor in the nucleus, MTA1s appears to intercept the estrogen receptor in the cell body and prevent it from making its way to the nucleus.

To see how this finding applied to cancer patients, Dr. Kumar and his research team, in collaboration with M. D. Anderson physicians Dr. Aysegul Sahin and Dr. Gabriel Hortobagyi, studied 31 patients whose tumors were classified as estrogen receptor positive or estrogen receptor negative. They found that MTA1s was four times higher in tumors classified as estrogen receptor negative by conventional methods. Moreover, they found these cells actually contained estrogen receptors, but that they were being trapped in the main body of the cell, the cytoplasm, by MTA1s.

"Currently, pathologists look for estrogen receptor in the nucleus of cancer cells," Dr. Kumar says. "If they don't find it there, they classify the tumor as estrogen receptor negative. However, some percentage of those tumors actually may have the functional estrogen receptor that is being sequestered in the cytoplasm by MTA1s. Currently, there is no way to distinguish between cells with no or low estrogen receptor in the nucleus and those with the estrogen receptor sequestered in the cytoplasm."

Further study showed that by deleting the portion of MTA1s that attaches to the estrogen receptor, they could restore functional estrogen receptors to the nucleus of cells in the laboratory.

"We have shown in tissue culture cells that we could restore the estrogen receptor to the nucleus," Dr. Kumar says. "The finding demonstrates that it may be possible to restore estrogen receptor responsiveness to breast cancer cells. Since we have defined at least one of the mechanisms that is responsible for retaining the estrogen receptor in the cytoplasm, it should be possible to find a small molecule to compete it out."

Currently, there is no way to restore estrogen responsiveness to breast cancer cells once it is lost.

M.D. Anderson Cancer Center has applied for a patent on the use of MTA1s for diagnosis and treatment of cancer.
-end-
Other M. D. Anderson researchers who contributed to the study include Dr. Rui-An Wang, Dr. Abhijit Mazumdar, Dr. Amjad H. Talukder, Dr. Mahitosh Mandal, Dr. Zhibo Yang, Dr. Rozita Bagheri-Yarmand, Dr. Sahin, Dr. Hortobagyi, Dr. Liana Adam, Dr. Christopher J. Barnes and Dr. Ratna K. Vadlamudi.

The research was supported by grants from the Susan G. Komen Breast Cancer Foundation and the National Institutes of Health.

University of Texas M. D. Anderson Cancer Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.