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BRCA1 Mutations Influence Cancer Cells’ Response to Drugs

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The Journal of the National Cancer Institutes has published results of a collaboration between Queens University, Belfast and Almac Diagnostics using the company’s Breast Cancer DSA™, to generate valuable new insight into the interactions between BRCA1 and estrogen receptor alpha (ERa).

It has been widely reported in the literature that BRCA1 linked breast cancers typically fail to express ER?, however the mechanism behind this link has remained obscure. ERa is the therapeutic target for antiestrogen therapies such as fulvestrant and tamoxifen, while BRCA1, a tumour suppressor gene, is associated with genetic predisposition to breast and ovarian cancers.

The Queens / Almac study has demonstrated that BRCA1 alters the response of breast cancer cells to fulvestrant therapy by directly modulating ERa mRNA expression.

“The initial clue that BRCA1 may directly regulate ERa at the mRNA level came from expression profiling studies utilizing the Almac Diagnostics Breast Cancer DSATM directly from Formalin Fixed Paraffin Embedded (FFPE) tumour samples” commented Prof Paul Harkin.

The array data demonstrated that ERa mRNA expression was 5.4-fold lower in tumors with BRCA1 mutations than in sporadic tumors and was subsequently confirmed by real time PCR. The study went on to demonstrate that BRCA1 directly regulates ESR1 expression through an Oct-1 dependent interaction with the ESR1 promoter.

Finally it was shown that expression of ERa in BRCA1-depleted breast cancer cells made the cells more sensitive to an antiestrogen drug Fulvestrant. They conclude that BRCA1 alters the response of breast cancer cells to antiestrogen therapy by directly influencing ERa expression.