The LOX Invasion: Stopping the Spread of Breast Cancer
Loss of Pdcd4 may sensitize tumors to hypoxia-induced invasion and/metastasis. In normal cells Pdcd4 levels are fairly high and inhibit expression of lysyl oxidase (LOX). As cells undergo hyperplasia, they often overexpress the AKT kinase which in turn marks Pdcd4 for proteosomal degradation. Loss of Pdcd4 thus results in loss of LOX inhibition. As the tumor grows and experiences a hypoxic microenvironment, LOX expression is further enhanced through a HIF1-dependent mechanism resulting in the extracellular matrix remodeling and, tumor invasion and metastasis.
Metastasis is the primary cause of death in breast cancer patients. In 10% of breast cancer diagnoses, the cancer has already spread to distant organs in the body. Although breast cancer has the potential to spread to almost any region of the body, the most common is the bone, followed by the lung and liver. Understanding the mechanisms for breast cancer invasion and metastasis is therefore vital for designing new therapies to prevent the spread of the disease.
Communication between tumor cells and their microenvironment helps to determine how a tumor will progress; going from normal to malignant to metastatic is driven not just by what's happening inside the tumor cell itself but by what's happening around it. Hypoxia, or decreased availability of oxygen, is an important characteristic of the microenvironment of solid tumors. In addition to being a consequence of the growth of a malignant tumor, hypoxia also acts to promote tumor development. Hypoxic conditions are known to affect the response of solid tumors to radiation and are associated with increased invasive and metastatic potential. Markers for hypoxia are expressed by 20-40% of invasive breast cancers.
Arti Santhanam, Ph.D., a fellow in the CCR Laboratory of Cancer Prevention, and her colleagues hypothesized that two proteins, Pdcd4 and LOX, play important and inter-dependent roles in breast cancer progression and metastasis. Pdcd4 is a protein expressed in all cells of the body and has been established as a tumor suppressor; its expression is often decreased in advanced, invasive cancers of the lung, breast, and colon. It has also been shown to regulate genes that affect the microenvironment. Gene profiling has implicated LOX as one such protein. Normal LOX activity is essential for maintaining the structural integrity of tissue, and increased LOX activity is associated with enhanced breast cancer cell invasion, especially under hypoxic conditions. In a recent paper published in Oncogene, Dr. Santhanam and her colleagues identified LOX as a target for Pdcd4. They demonstrated that Pdcd4 inhibits LOX expression and invasion of breast cancer cells. By depleting cells of Pdcd4, LOX protein levels increased concomitant with invasion of breast cancer cells. Inhibiting LOX activity reversed these effects.
While LOX has been previously implicated in hypoxia-mediated breast cancer metastasis, the role of Pdcd4 in hypoxia is unknown. To determine the effect of Pdcd4 in hypoxia-induced invasion, the researchers measured the invasive ability of aggressive breast cancer cells and compared it to that of breast cancer cells depleted of Pdcd4 under both normal and hypoxic conditions. Under hypoxic conditions, cells depleted of Pdcd4 showed similar levels of invasion to the naturally aggressive breast cancer cells. Blocking LOX expression reversed these effects. Hypoxia did not affect cells with normal levels of Pdcd4.
Dr. Santhanam and her colleagues propose a model where Pdcd4 inhibits LOX expression and thus the invasive potential of cells. Loss of Pdcd4 during tumor progression results in increased LOX expression and tumor cell invasion; this effect is further enhanced when tumors are exposed to hypoxic conditions, such as occurs in the tumor microenvironment. These findings are the first to implicate loss of Pdcd4 in a hypoxic response in breast cancer. The identification of Pdcd4 as a regulator of hypoxic response suggests its potential in assessing disease outcome. The authors suggest that perhaps expression of the Pdcd4 protein or increased expression of Pdcd4 may be a viable target for preventing cancer metastasis in response to hypoxia.Summary Posted: Tue, 06/01/2010
Oncogene. 2010. May 24. Advance online publication PubMed Link