Breast cancer has the propensity to disseminate to distant organs, even before diagnosis of the primary tumor, where it can remain in a clinically undetectable state for many years. Eventual growth of these disseminated tumor cells (DTCs) into metastases, also known as distant recurrence, occurs in 20-30% of patients. This is the overwhelming cause of breast cancer mortality; metastatic breast cancer is not curable. The perplexing period of clinical "dormancy" before recurrence is poorly understood, but almost certainly requires tumor cells to adapt to and modify their new environment, and to evade immune-mediated killing.
DTCs are detectable in the bone marrow, where they can undergo dormancy and reawakening. Because of difficulties in tissue sampling, it is unknown how often DTCs exist in other tissues, and/or whether bone marrow DTCs migrate and give rise to metastases in other sites. However, it is clear that bone metastases are the most common site of recurrence in breast cancer. Although patients do not die directly from bone metastasis, bone lesions are the most common first site of recurrence, and median survival time from diagnosis of bone metastasis is only 2-3 years. Because skeletal disease has profound systemic effects, it is thought that bone metastases can influence cancer progression in other sites. Breast cancer bone metastases are primarily osteolytic due to activation of bone-resorbing resident macrophages known as osteoclasts. Osteoclasts are the key players in a “vicious cycle” whereby tumor-derived factors stimulate osteoclasts to release systemic tumor-promoting factors from the bone matrix and from the activated osteoclasts themselves. In this way, a feed-forward loop is created between tumor cells and osteoclasts, which leads to increased tumor growth and osteolysis. Importantly, several of these factors have recently been shown to have long-ranging systemic effects, promoting tumor growth and metastatic seeding not just locally, but across the body. Furthermore, published data are accumulating that show that osteoclasts can have a potent effect on immune responses in cancer
Using mouse models, we discovered that the RON receptor tyrosine kinase is a key mediator of breast cancer outgrowth at metastatic sites. Although RON can play a role in the tumor cells themselves, we found that the critical role for RON is in the host microenvironment. RON functions in osteoclasts to promote their activation in a RANKL-independent manner, converging on SRC signaling to mediate bone resorption. Genetic knockout or inhibition of RON protects bones from osteolysis, reduces metastasis at other sites, and protects from osteoporosis. Treatment of cancer patients with a RON inhibitor in a first-in-human Phase I clinical trial improved bone turnover markers compared to baseline, suggesting that RON inhibitors could potentially be used to protect from bone destruction and metastasis. This idea is currently being tested in a Phase Ib clinical trial in breast cancer patients with bone metastasis.


Alana Welm, PhD

Susan G. Komen Scholar, and
Associate Professor
Department of Oncological Sciences
University of Utah View Full Bio



ACPEThe University of North Texas Health Science Center is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.


This knowledge-based activity has been assigned UAN 0845-9999-18-094-L01-P and will award 1.00 contact hour (0.100 CEUs) of continuing pharmacy education credit in states that recognize ACPE providers.

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The University of North Texas Health Science Center is accredited by the American Osteopathic Association to award continuing medical education to physicians.

The University of North Texas Health Science Center has requested that the AOA Council on Continuing Medical Education approve this program for 1.00 hour of AOA Category 2A CME credits. Approval is currently pending.

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the University of North Texas Health Science Center, and Komen of Greater Fort Worth. The University of North Texas Health Science Center is accredited by the ACCME to provide continuing medical education for physicians.

The University of North Texas Health Science Center designates this live activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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ACGME Competencies

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IOM Competencies

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UNT Health Science Center is an approved provider of continuing nursing education by the Texas Nurses Association - Approver, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.

This activity provides up to 1.00 contact hour.


This activity is jointly provided by the University of North Texas Health Science Center and Komen of Greater Fort Worth.