# MALIGNANCY-ASSOCIATED HYPERCALCEMIA

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 1992 · $175,849

## Abstract

A parathyroid hormone (PTH) like protein implicated in the pathogenesis
of hypercalcemia in malignancy has recently been identified. It has
isoforms of 139 and 141 amino acids and is strongly homologous with PTH
only at its amino-terminus. The PTH-like protein (PLP) is expressed by
squamous and renal carcinomas, binds with high affinity to the PTH
receptor in kidney and bone, and is a potent hypercalcemic substance.
Although it thus has all the properties predicted of a humoral mediator
of hypercalcemia, PLP has yet to be identified as a circulating factor in
malignancy-associated hypercalcemia. Besides solid tumors, HTLV-1
infected malignant lymphocytes express PLP, and clinical dta suggest a
humoral role in adult T-cell leukemia, which if frequently complicated by
hypercalcemia. We have developed a radioimmunoassay (RIA) to measure PLP
is serum, and preliminary results indicate that PLP is detectable in
hypercalcemic patients with squamous carcinoma, but not in normal
subjects. The further RIA studies proposed are intended to forge the
final link in a chain of evidence that implicates PLP in humoral
hypercalcemia. PLP may also have a second role in the pathogenesis of
hypercalcemia, inducing local osteolysis when secreted at low levels by
betastatic tumors in bone. In view of expression of PLP by lactating
mammary tissue and its isolation from a single breast carcinoma, we will
screen for expression of PLP in breast carcinoma, a tumor in which
hypercalcemia is thought to result from local osteolysis.

PLP is also expressed in normal embryonic and adult tissues, including
skin and lactating breast. Its potency and its remarkable evolutionary
conservation (human and rat PLP are identical through 110 amino acids)
suggest a significant physiological role for PLP. That it is not
detectable in normal serum raises the possibility that these
physiological effects are local. Expression in differentiating
keratinocytes and embryonal carcinoma cells suggests that PLLP may be a
differentiation factor, a possibility that we will explore in both
systems. At the same time, we will attempt uncover paracrine targets for
PLP by localizing its receptors autoradiographically. We have begun to
study how the secretion of PLP is controlled by calcium, cytokines and
hormones, where the control of its synthesis is exerted at the cellular
level, and how PLP is processed for secretion. Besides their implications
for the physiological function of PLP, these studies will cast light on
the reasons for its excessive secretion in malignancy.

## Key facts

- **NIH application ID:** 3172531
- **Project number:** 5R01CA034738-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **SAM.gov UEI:** KMH5K9V7S518
- **Principal Investigator:** GORDON J STREWLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $175,849
- **Award type:** 5
- **Project period:** 1986-08-15 → 1994-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172531

## Citation

> US National Institutes of Health, RePORTER application 3172531, MALIGNANCY-ASSOCIATED HYPERCALCEMIA (5R01CA034738-07). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172531. Licensed CC0.

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