The Parathyroid Hormone–Related Protein (PTHrP) Gene: Use of Downstream TATA Promotor and PTHrP 1–139 Coding Pathways in Primary Breast Cancers Vary with the Occurrence of Bone Metastasis

Abstract

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5-and 3-untranslated sequence amounts of parathyroid hormone-related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (

Parathyroid Hormone Related Protein: A Marker of Breast Tumor Progression and Outcome

“…Our semi-quantitative RT-PCR studies, which are considerably more accurate than immunochemistry, showed that PTHrP mRNA was present in 82% of primary breast cancers (Bouizar et al 1993). We also found PTHrP mRNA in significantly more (97%) patients with primary breast cancer who subsequently developed bone metastases than those who remained free of metastases or developed metastases in soft tissues (Bouizar et al 1993(Bouizar et al , 1999. Patients with cancer often have severe hypercalcemia (Strewler, 2000).…”

“…Significantly more cells in breast cancer tumors and metastases that are rich in PTH/PTHrP receptor mRNA and protein are labeled with antibodies to the proliferation marker Ki-67, suggesting that this receptor is associated with the increased proliferation of these tumors (Downey et al 1997). We found high concentrations of PTHrP mRNA in primary breast cancers of 110 patients who later develop bone metastases (Bouizar et al 1993(Bouizar et al , 1999. It is therefore very likely that the peptide influences aspects of the disease that precede metastasis to bone.…”

“…A retrospective RT-PCR study showed increased transcripts of PTHrP in the primary tumors of patients who subsequently developed bone metastases (Bouizar et al, 1993). The results of an extension of this study to a larger cohort suggested that transcripts encoding the 139-residue isoform were overexpressed in tumors that had metastasized to bone (Bouizar et al 1999;Guise et al 2002 ). PTHrP produced by breast cancer cells may facilitate the development of skeletal metastases by enhancing the survival of tumor cells in bone, or by promoting the invasion of bone by tumor cells (Bundred et al, 1992).…”

“…P1 and P3 are canonical TATA promoters (Mangin et al, 1990;Campos et al, 1992;Suva et al, 1989) and initiate transcription at exons 1 and 4 respectively, while P2 is a GC-rich promoter that initiates transcription upstream of exon IC (Vasavada et al, 1993). Evaluation of PTHrP alternative promoter usage by qualitative (Southby et al, 1995 and and quantitative reverse transcription RT-PCR (Bouizar et al, 1999;Richard et al, 2003) revealed high concentrations of P3-initiated transcripts in most tumors, including breast cancers (Bouizar et al, 1999) and many tumor cell lines (Cataisson et al, 2003). The amino acid sequences encoded by only two of the 9 exons in the human gene are present in all transcripts.…”

“…About 60% of primary breast neoplasms contain PTHrP immunoreactivity, as do more than 90% of metastatic foci in bone (Southby et al 1990, Downey et al 1997. And patients with primary breast cancer who later develop bone metastases have elevated plasma PTHrP mRNA concentrations (Bouizar et al 1993(Bouizar et al , 1999. The presence of PTHrP immunoreactivity in many breast cancers has led to the suggestion that the peptide has an autocrine effect on tumor growth (Iezzoni et al 1997).…”