Scientists Identify Protein That Makes A Drug Efficient In Breast Cancer Patients

Scientists at Wake Forest Baptist Medical Center have identified a protein which can help in restoring the hormone-blocking drug effectiveness against breast cancer.

The team has found that by down regulating the gene expression of GRP78 protein, the estrogen-positive (ER+) tumor sensitivity to the anti-tumor drugs can be restored. The finding of this study was also recently published in Cancer Research.

The study was co-authored by experts from Georgetown University Medical Center and the National Institute of Health.

The findings of the study will help in restoring the effects of cancer drugs, such as tamoxifen and fulvestrant, which under successful treatment block the hormone estrogen receptors in the ER+ cancer cells, which are required by the cancer cells to grow.

GRP78 protein which is abbreviated for glucose-regulated protein is found in the lumen of the endoplasmic reticulum and has a role in folding of proteins and monitoring protein transport through cells. However, their novel role in affecting drug sensitivity for breast cancer has now been found.

Breast cancer is the most commonly diagnosed cancer in women at a global level. In the US alone, over 24,660 new cases have been reported in 2016.

Comparing to other types of cancer, the prognosis of breast cancer is good and the 5-years survival rate in the women diagnosed at stage I with breast cancer is over 90%. Those who are diagnosed at stage II have a 5-year survival rate of 93%, while those who are at stage III of the disease have a 5-year survival rate of 72%.

Awareness of breast self-exam, timely carried out mammography, breast removal and effective drugs have positively influenced the survival rate of breast cancer, many chemotherapy drugs fail to treat the patients. It is estimated that about 50% of these tumors develop resistance to the hormone blocking treatments, which facilitates tumor metastasis.

The breast cancer is stratified into four types which include endocrine receptor-positive (estrogen or progesterone receptors), HER2-positive (human epidermal growth factor receptor 2), triple positive, (meaning that the tumor is positive for estrogen receptors, progesterone receptors and HER2) and triple negative (suggesting that the tumor is negative for estrogen receptors, progesterone receptors and HER2).

Out of these cancers, the hormone-sensitive breast cancer cells carry hormone receptors which interact with the respective hormones to multiply.

The classification of breast cancer type is of utmost importance for the oncology experts because this is a primary determinant of drug efficacy. Thereby, clinicians perform tests and biopsies to learn about the cancer type and prescribe the medications accordingly.

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According to the American Cancer Society, the estrogen-positive (ER+) type of breast cancer is the most common form of the cancer and 2 out of 3 diagnosed cases of breast cancer are receptor positive. These receptor positive are mostly ER+ and in other cases, the cancer is receptive to both estrogen and progesterone.

From previously conducted studies, the scientists learnt that increased levels of glucose-regulated protein 78 (GRP78) are present in tumor cells and they play a vital role in eliciting drug resistance in tumor cells, observed under laboratory condition.

Getting direction from this study, these scientists set out to determine the effect of this protein in mice model. To start off with, they observed the GRP78 target molecule called morpholino, which was responsible for modifying gene expression of this protein.

This molecule was found to successfully inhibit the protein expression which led them to restore drug sensitivity.

The study leader, Katherine Cook, PhD, assistant professor at the institute, said that morpholinos are candidate drugs currently under clinical trial to treat prostate cancer, but it was the first time when the gene expression manipulation of the target protein by morpholinos is found to have a role in restoring the efficacy of chemotherapy.

In addition to this, the researchers found from the metabolic analysis of breast cancer cells that other than suppressing the gene expression, encoding for the protein also has a role in cellular lipid metabolism. This role was carried out by increasing intracellular concentrations of essential polyunsaturated fats, including linoleic acid.

For confirming this novel finding, the cancer induced mice were given different dosages of linoleic acid and interestingly, the effects of this approach was identical to targeting GRP78 to drug sensitivity restoration.

Cook added that this is yet another important finding which has linked fatty acid regulation and its role in cancer management. Thrilled by the association, she 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 further investigating the dietary effects on breast cancer progression by using different types of fatty acids and diets.

Earlier in September, the scientists from the University of Illinois successfully found a gene variant encoding protein XPO1 which has an integral role in drug resistance to tamoxifen. Down regulating the expression of the genes resulted in enhancing the patient’s sensitivity to the drug.

With the progress in restoring drug sensitivity in breast cancer patients and understanding the genetic causes of therapy failure, the disease burden of tumor metastatic is likely to reduce in future.

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