Hpr6 (heme-1 domain protein) regulates the susceptibility of cancer cells to chemotherapeutic drugs.

Cancer cells have varying levels of susceptibility to chemotherapeutic agents, and the proteins that direct drug susceptibility are promising targets for intervention in cancer. Hpr6 (heme-1 domain protein)/PGRMC1 (progesterone receptor membrane component 1) is overexpressed in tumors, and Hpr6 is the human homolog of a budding yeast damage resistance gene called Dap1p. Cells lacking Dap1p are damage-sensitive, and we have found that inhibition of Hpr6 expression by RNA inhibition (RNAi) increases sensitivity of breast cancer cells to chemotherapeutic drugs.

A novel group of genes regulates susceptibility to antineoplastic drugs in highly tumorigenic breast cancer cells.

Doxorubicin is an anthracycline antibiotic used for cancer chemotherapy. The utility of doxorubicin is limited by its inability to kill all of the cells within a tumor and by resistant cells emerging from the treated population. We have screened for genes that regulate doxorubicin susceptibility in highly tumorigenic breast cancer cells by cDNA microarray and RNA interference (RNAi) analysis, and we have identified genes associated with both proliferation and cell cycle arrest after doxorubicin treatment.

Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors.

Objective: Hpr6 (heme-1 domain protein/human progesterone receptor) is one of a family of proteins that are implicated in progesterone metabolism, resistance to genotoxic agents and steroid biosynthesis. Because these processes are frequently misregulated in tumors, we have examined the expression of Hpr6 in a group of clinical tumor samples and cancer cell lines.

Methods: Hpr6 expression was analyzed by Western blot in extracts from breast, cervix, colon and thyroid cell lines and in nonmalignant and adjacent tumor tissue from breast, colon and thyroid.

Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae.

Alkylating agents chemically modify DNA and cause mutations that lead to cancer. In the budding yeast Saccharomyces cerevisiae, resistance to the alkylating agent methyl methanesulfonate (MMS) is mediated in part by Dap1p (damage resistance protein 1). Dap1p is related to cytochrome b5, which activates cytochrome P450 proteins, elevating the metabolism of lipids and xenobiotic compounds.