Transcription Factor Deficit Spurs Tumor Development

A team of British cancer researchers found that the transcription factor proline-rich homeodomain protein (PRH/HHEX) played a tumor suppressive role in the breast, and they provided an explanation for the finding that low PRH mRNA levels were associated with a poor prognosis in breast cancer.

Breast tumors progress from hyperplasia to ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). In order to study the role of the PRH/HEX transcription factor in this progression, investigators at the University of Birmingham (United Kingdom) adapted a population of human breast cancer MCF-7 cells to under or over produce PRH/HEX.

They reported in the June 12, 2017, online edition of the journal Oncogenesis that transcriptionally inactive phosphorylated PRH was elevated in DCIS and IBC compared with tissues in the normal breast. To determine the consequences of PRH loss of function in breast cancer cells, they induced PRH depletion in their line of MCF-7 cells. They showed that PRH depletion resulted in increased MCF-7 cell proliferation in part at least due to increased vascular endothelial growth factor signaling. Moreover, they demonstrated that PRH depletion increased the formation of breast cancer cells with cancer stem cell-like properties.

In a mouse model, PRH overexpression inhibited the growth of mammary tumors. Taken together, these data indicated that PRH played a tumor suppressive role in the breast, and they provided an explanation for the finding that low PRH mRNA levels were associated with a poor prognosis in breast cancer.

Senior author Dr. Padma Sheela Jayaraman, senior lecturer in cancer biology at the University of Birmingham, said, "PRH is a protein that controls and regulates when genes are switched on or off. However, prior to our research, the role of this protein in breast cancer has been poorly understood. In the laboratory, we found that when PRH protein levels are reduced in a breast tumor the cells are more able to divide, speeding up the progression of the tumor. Moreover, we identified some of the genes which are regulated by PRH and specifically contribute to the increased cell division."

"We made the significant finding that high levels of PRH actually blocked the formation of the tumors, therefore our data suggests that PRH can block tumor formation in some breast cancers," said Dr. Jayaraman. "We propose that monitoring PRH protein levels or activity in patients with breast cancer could be particularly important for assessing their prognosis. In addition, since PRH is known to be important in multiple cell types, this work has important implications for other types of cancer."

Related Links:
University of Birmingham