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Inhibiting the GRP78 Protein in Estrogen Receptor-Positive Breast Cancer Reduces Resistance to Treatment

Health In Focus   - G J E 4
Highlights
  • Breast cancer is one of the most common type of cancer that affects women.
  • The most common type of breast cancer is the estrogen-receptor positive or ER+ breast cancer where the cancer cells grow in the presence of hormone estrogen.
  • Tamoxifen blocks the estrogen receptors and prevents estrogen from binding to them, but the main drawback of this treatment is that the cancer cells develop resistance to the drug, making it less effective in due course.
  • A recent study has determined the role of a protein GRP78, in enhancing and restoring sensitivity to estrogen-blocking drugs.
The role of a protein in enhancing and restoring sensitivity to estrogen-blocking drugs in estrogen-receptor positive or ER+ cancer, has been determined. The research has been published in Cancer Research.
Inhibiting the GRP78 Protein in Estrogen Receptor-Positive Breast Cancer
Reduces Resistance to Treatment
Inhibiting the GRP78 Protein in Estrogen Receptor-Positive Breast Cancer Reduces Resistance to Treatment
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Breast cancer develops when the cells in the breast grow out of control. It often starts as a painless lump in which the cells grow abnormally, invade the surrounding tissue and spread to distant areas of the body.

‘Drugs targeting protein GRP78, certain dietary measures like polyunsaturated fatty acid supplementation may help in increasing sensitivity of estrogen-receptor positive breast cancer to estrogen-blocking drugs.’
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Most breast cancers originate from the cells that line the ducts that carry milk to the nipples (ductal cancers). Some originate in the glands that produce milk (lobular cancers). Other tumors like sarcomas and lymphomas may also be noted in the breast.

In the United States, breast cancer is the most common type of cancer that affects women after skin cancer. According to the American Cancer Society, breast cancer estimates for 2016 are:
  • Around 246, 660 new cases of invasive breast cancer
  • Around 61,000 new cases of non-invasive breast cancer
  • Around 40,450 women are expected to die due to breast cancer
In India, according to the Indian Council of Medical Research, there will be around 1.5 lakh new cases of breast cancer in 2016.

To know what kind of treatment is most effective, breast cancers are divided into following types:
  • Endocrine-receptor positive - The cancer cells have receptors for either estrogen or progesterone..
  • HER2-positive - These cancers have cells with receptors for the protein HER2.
  • Triple positive - The cancer cells have receptors for estrogen, progesterone and HER2.
  • Triple negative - The cancers have cells that do not have receptors for estrogen, progesterone and HER2.
Around 80% of breast cancers detected are estrogen-receptor positive or ER+ cancers. This type of breast cancer has the most favorable prognosis. The breast cancer cells receive signals from estrogen that promote their growth or, in simple words, the cancer cells grow in the presence of estrogen hormone. These cancers can be treated by lowering the estrogen level or blocking the action of estrogen that fuels the growth of cancer cells.

The medications tamoxifen and fulvestrant are used in the treatment of ER+ breast cancers. These medications block the estrogen receptors on the breast cancer cells and prevent estrogen from binding to them. One of the main drawbacks of this treatment is that though initially responsive, the cancer cells later develop resistance making medicines less effective.

Scientists at the Wake Forest Baptist Medical Center conducted experiments in an animal model and found that targeting a glucose-regulated protein 78 (GRP78), which is elevated in breast cancer tumors, could help to enhance and restore sensitivity to estrogen-blocking drugs in ER+ breast cancers.

For their study, researchers initially used a GRP78 targeting molecule called morpholino. They found that morpholino successfully inhibited GRP78 and helped in restoring sensitivity to tamoxifen in resistant tumors.

"Morpholinos are candidate drugs already being used to target other proteins in clinical trials to treat prostate cancer, but this is the first time inhibiting the gene expression of GRP78 with these agents may have potential to overcome resistance to chemotherapy," said Katherine Cook, Ph.D., assistant professor at Wake Forest School of Medicine, a part of Wake Forest Baptist, Scid and the study's lead author.

The researchers also found that suppressing GRP78 increased the intracellular concentrations of essential polyunsaturated fats, including linoleic acid. They therefore fed the tumor-bearing mice with different doses of linoleic acid, which restored the tamoxifen sensitivity to the tumors. This study highlights the importance of fatty acid regulation in cancer, Cook said. "While drugs against GRP78 protein are further along as a potential cancer therapy, dietary measures such as polyunsaturated fatty acid supplementation may also enhance therapeutic sensitivity."

The researchers are currently looking at the role of diet on breast cancer in an animal model using different types of fatty acids and diets to see whether they have an effect on tumor growth or endocrine therapy responsiveness. 

Tips to Lower Risk of Breast Cancer
  1. Eat healthy - Eating plenty of fresh vegetables and fruits and avoiding saturated and trans-fat.
  2. Alcohol consumption and smoking - Alcohol has shown to increasethe risk of breast cancer. Moderation of alcohol consumption and avoiding tobacco lower the risk of several types of cancers.
  3. Exercise - Physical activity has shown to lower the risk of several type of cancers. Women who are physically active for at least 30 minutes in a day have low risk of developing breast cancer.
  4. Maintain healthy weight - Being overweight can increase the risk of many types of cancers especially after menopause.
  5. Breastfeed - Breastfeeding for more than a year has shown to lower the risk of breast cancer.
  6. Clinical Breast Examination - Getting breasts examined by a professional helps in detecting early changes and abnormalities that could suggest signs of breast cancer like change in the size and shape of breast, puckering or dimpling of the skin, changes in the nipples or any sort of discharge from them.
  7. Screening - Preventive screening with mammography after 40 years of age helps in ruling out or early detection of breast cancer.
  8. Preventive Breast Cancer Drugs - Tamoxifen, which until now has only been used for breast cancer treatment lowers the risk of the disease by 0% to 40%. It can be used to reduce cancer risk in high-risk women.
References
  1. What Is Breast Cancer? - (http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics)
  2. Hormone Receptor Status - (http://www.breastcancer.org/symptoms/diagnosis/hormone_status)
  3. Breast Cancer - (http://cancerindia.org.in/cp/index.php/know-about-cancer/breast-cancer#early-detection)
Source: Medindia
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