Discussion

Similarity Difference
Breast cancers in both species are metastatic. Most tumors mouse metastasize to the lung. Most human metastasize to the regional lymph nodes.

Both human and murine mammary tumors frequently develop metastatic disease. Examples are found here: human and mouse

Mouse mammary tumors generally metastasize to the lungs. Some authors find that the mammary cells in the lung do not extravasate.

Genetically Engineered Mice with mammary cancer also develop pulmonary metastases. They have been used as a model system for mammary metastases.

Human breast cancers metastasize to the regional lymph nodes and systemically in the liver, lungs and bone. The bone metastases are the most difficult symptom to manage.


Mouse mammary tumors generally metastasize to the lungs. Some authors find that the mammary cells in the lung do not extravasate.

  1. A survey of in vivo growth characteristics and spontaneous metastasizing potentials of C3H mouse mammary tumors.
    Vaage J
    Int J Cancer 1989 May 15;43(5):910-4

    This investigation examined the relationship between spontaneous metastasizing potential, immunogenicity and growth rate in 34 C3H/He mammary carcinomas. The main purpose of our studies was to examine the hypothesis that a tumor's metastasizing potential is affected by its immunogenicity. The tumors were studied during serial intra-mammary transplantations, starting with tissue from autochthonous, spontaneous pulmonary metastases. The results show that there was no correlation between metastasizing potential and tumor immunogenicity, and no correlation between metastasizing potential and tumor growth rate. Moreover, metastasizing potential was not related to invasive behavior, because histological examination showed that all of the metastases grew extensively within pulmonary vessels and displayed no tendency to active extravasation.

  2. Spontaneous metastasis from primary C3H mouse mammary tumors.
    Vaage J, Harlos JP
    Cancer Res 1987 Jan 15;47(2):547-50

    The normal incidence of metastasis was determined in 207 C3H/He and 42 C3Hf/He mice with spontaneous mammary tumors. The effects of early versus delayed surgical removal of the tumors on the incidence of metastasis were studied in the C3H/He mice. The presence of metastases was determined by histological examination, primarily of the lungs. The incidence of metastasis was proportional to the size the primary tumors were allowed to reach before surgery, with the highest incidence in mice not surgically cured. Tumors that developed early in the life of the mice had the greater tendency to metastasize. Immunogenic and non-immunogenic tumors occurred with similar frequency among 16 metastasizing tumors tested. Primary tumors and their metastases were equally immunogenic. All of 95 metastasizing adenocarcinomas grew extensively within pulmonary vessels with no tendency for active extravasation. In contrast, each of six metastasizing mammary sarcomas extravasated actively and probably extravasated early because intravascular growth was never observed.

  3. Mammary carcinoma cell lines of high and low metastatic potential differ not in extravasation but in subsequent migration and growth.
    Morris VL, Koop S, MacDonald IC, Schmidt EE, Grattan M, Percy D, Chambers AF, Groom AC
    Clin Exp Metastasis 1994 Nov;12(6):357-67

    We examined the extravasation and subsequent migration and growth of murine mammary tumor cell lines (D2A1 and D2.OR) which differ in their metastatic ability in lung and liver, invasiveness in vitro and expression of the cysteine proteinase cathepsin L. In light of the differences in invasiveness and cathepsin L expression, we hypothesized that during hematogenous metastasis the two cell lines would differ primarily in their ability to extravasate. We used in vivo videomicroscopy of mouse liver and chick embryo chorioallantoic membrane to examine the process and timing of extravasation and subsequent steps in metastasis for these cell lines. In contrast to our expectations, no differences were found between the cell lines in either the timing or mechanism of extravasation, at least 95% of cells having extravasated by 3 days after injection. However, after extravasation, the more metastatic and invasive D2A1 cells showed a greater ability to migrate to sites which favor tumor growth and to replicate to form micrometastases. These studies point to post-extravasation events (migration and growth) as being critical in metastasis formation.


Genetically Engineered Mice with mammary cancer also develop pulmonary metastases. They have been used as a model system for mammary metastases.

  1. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis.
    Kim H, Muller WJ
    Exp Cell Res 1999 Nov 25;253(1):78-87

    A number of receptor systems have been implicated to play an important role in the development and progression of many human cancers. The epidermal growth factor (EGF) receptor tyrosine kinase family has been found to consistently play a leading role in tumor progression. Indeed, in human breast cancer cases the prognosis of a patient is inversely correlated with the overexpression and/or amplification of this receptor family. Furthermore, downstream signaling components such as the Src kinases, PI3'K, and the Ras pathway display evidence of deregulation that can accelerate tumor progression. The transgenic mouse system has been ideal in elucidating the biological significance of this receptor family in mammary tumorigenesis. Molecular events involved in mammary tumorigenesis such as ligand binding, receptor dimerization, and the activation of downstream pathways have been addressed using this system. Although there are many molecular steps that appear to drive each stage of tumor development, the EGF receptor family appears to play a causal role in the progression to a transformed phenotype. Copyright 1999 Academic Press.

  2. Transgenic models of breast cancer metastasis.
    Dankort DL, Muller WJ
    Cancer Treat Res 1996;83:71-88

    Review Article

  3. Microcirculation and metastasis in a new mouse mammary tumor model system
    Cheung ATW, Young LJT, Chen PCY, Chao CY, Ndoye A, Barry PA, Muller WJ, Cardiff RD
    International Journal of Oncology

    Two new metastatic mouse mammary tumor transplant lines have been established in nude mice. The Met-1 line, with the polyoma virus middle T (PyV-MT) transgene, metastasized with 100% efficiency. The Db-7 line, expressing a PyV-MT transgene mutated at positions 315 and 322, metastasized with 8.8% efficiency. Histology and computer-assisted intravital microscopy demonstrated that internal microcirculation in Met-1 was more complex than Db-7; Met-1 exhibited higher microvessel density and tortuosity (P < 0.0001). These indices of microvascular complexity correlated with the higher Met-1 metastatic rate (P < 0.0001). These two transplantable lines will be useful for investigating the complex relationship between angiogenesis and metastasis.
    (not in PubMed)


Human breast cancers metastasize to the regional lymph nodes and systemically in the liver, lungs and bone. The bone metastases are the most difficult symptom to manage.

  1. Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma: a multicenter study.
    Weaver DL, Krag DN, Ashikaga T, Harlow SP, O'Connell M
    Cancer 2000 Mar 1;88(5):1099-107

    BACKGROUND: Axillary lymph node status is a powerful prognostic factor in breast carcinoma; however, complications after axillary lymph node dissection are common. Sentinel lymph node biopsy is an alternative staging procedure. The sentinel lymph node postulate is that tumor cells migrating from the primary tumor colonize one or a few lymph nodes before colonizing subsequent lymph nodes. To validate this hypothesis, the distribution of occult and nonoccult metastases in sentinel and nonsentinel lymph nodes was evaluated. METHODS: Original pathology material was reviewed from 431 patients enrolled on a multicenter validation study of sentinel lymph node biopsy in breast carcinoma patients. Paraffin embedded tissue blocks of sentinel and nonsentinel lymph nodes were obtained for 214 lymph node negative patients. Additional sections from 100 and 200 &mgr;m deeper into the paraffin block were examined for the presence of occult metastatic carcinoma. Both routine and cytokeratin immunohistochemical stains were employed. RESULTS: Metastases were identified in 15.9% of sentinel lymph nodes and 4.2% of nonsentinel lymph nodes (odds ratio [OR] 4.3[ P < 0.001]; 95% confidence interval [95% CI], 3.5-5.4). Occult metastases were identified in 4. 09% of sentinel lymph nodes and 0.35% of nonsentinel lymph nodes (OR 12.3 [P < 0.001]; 95% CI, 5.6-28.6). The overall case conversion rate was 10.3%. All the occult metastases identified were < or = 1 mm in greatest individual dimension. The likelihood (OR) of metastases in nonsentinel lymph nodes was 13.4 times higher for sentinel lymph node positive than for sentinel lymph node negative patients (P < 0. 001; 95% CI, 6.7-28.1). CONCLUSIONS: The distribution of occult and nonoccult metastases in axillary lymph nodes validates the sentinel lymph node hypothesis. In addition, pathology review of cases confirmed the authors' previously reported finding that the sentinel lymph nodes are predictive of the final axillary lymph node status. Occult metastatic disease is more likely to be identified in sentinel lymph nodes, allowing future studies to focus attention on one or a few sentinel lymph nodes. However, the relation between occult metastatic disease in sentinel lymph nodes, disease free survival, and overall survival must be evaluated prior to endorsing the intensive analysis of sentinel lymph nodes in routine practice. [See editorial on pages 971-7, this issue.] Copyright 2000 American Cancer Society.

  2. Frequency of first metastatic events in breast cancer: implications for sequencing of systemic and local-regional treatment.
    Thames HD, Buchholz TA, Smith CD
    J Clin Oncol 1999 Sep;17(9):2649-58

    PURPOSE: The sequencing of treatment for early breast cancer is controversial. The purpose of this study was to quantify the risk of delaying surgery, using estimates of the frequency of first metastases from breast primary tumors. PATIENTS AND METHODS: The probability that 560 (node-negative), 657 (with one to three positive nodes), and 505 (with more than three positive nodes) women treated without adjuvant chemotherapy would be free of distant disease at presentation was fit to a mathematical model of the seeding of distant metastases and combined with estimates of the growth rate to calculate the frequency of first distant disseminations per month. RESULTS: Frequencies of first distant metastases were approximately 1% to 2% per month, 2% to 4% per month, and 3% to 6% per month in T1 patients who were node-negative, had one to three positive nodes, or more than three positive nodes, respectively. As a result, the typical patient with T1 disease, who has a 70% to 80% chance of being free of distant disease, runs a 1% to 4% risk of distant dissemination for each month surgery is delayed. Assuming a 30% reduction in mortality caused by adjuvant chemotherapy, the model predicts that T1 patients treated with neoadjuvant chemotherapy would potentially have a higher rate of distant metastasis development than those treated with an initial surgical resection followed by adjuvant chemotherapy. CONCLUSION: We formulate the hypothesis that optimal sequencing of surgery and systemic treatment of breast cancer may be size-dependent, with a disadvantage or no benefit from neoadjuvant treatment for T1 patients but an increasing benefit with increasing size of the primary tumor.

  3. Liver metastases: can our understanding of their biology and prognostic value contribute to a strategy for optimum therapeutic management?
    Pritchard KI
    Eur J Cancer 1997 Aug;33 Suppl 7:S11-4

    Breast cancer is most likely to recur in soft tissue, liver, lungs and bone. The development of visceral disease, in particular liver disease, carries a poorer prognosis than the development of soft tissue or bony disease. Traditionally, liver metastases were believed to respond more poorly to hormonal approaches than other metastatic sites; although many studies of hormonal agents document a response in liver metastases in at least a proportion of the patients treated. Chemotherapeutic agents are generally considered the first-line of approach for women who have developed liver metastases from breast cancer, however. No well designed randomised studies have yet been carried out to compare the effects of various chemotherapeutic approaches using response in liver as a specific outcome. Many practitioners believe, even if this belief is not well documented in studies, that anthracyclines are more likely to produce shrinkage of liver metastases than some of the more traditional regimens such as cyclophosphamide/methotrexate/5-fluorouracil. More recently, it has been suggested from phase II data that liver metastases may respond more rapidly and completely to some of the newer agents such as the taxoids. Even in the setting of very aggressive chemotherapy, however, liver metastases retain their poor prognosis. Both disease characteristics and systemic adjuvant therapy have been linked to the site of recurrence of disease and considerable research into the molecular mechanisms mediating the distribution of metastases has been carried out. Despite the poor prognosis for patients with liver metastases, many new avenues are currently being explored to better understand and control this situation and, perhaps, to lead to the development of new treatment strategies for patients with this disease.

  4. Cellular and molecular basis of preferential metastasis of breast cancer to bone.
    Yoneda T
    J Orthop Sci 2000;5(1):75-81

    Bone is one of the most preferential target sites for cancer metastasis. Breast cancer has a predilection for spreading to bone, and bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. None of the currently available therapies is effective for curing bone metastases in these patients. Elucidation of the cellular and molecular mechanism by which breast cancer selectively spreads to bone is essential for the development of mechanism-based effective and specific therapeutic interventions for this deleterious complication in breast cancer. Here, two questions are addressed to study the mechanism of breast cancer metastasis to bone: (1) What makes bone a preferential target site of metastasis? (2) What makes breast cancer able to colonize bone? (3) An animal model in which intracardiac inoculation of breast cancer cells selectively causes osteolytic bone metastases was developed. Experimental results obtained using this unique in-vivo model of bone metastasis are described and discussed.

  5. British Association of Surgical Oncology Guidelines. The management of metastatic bone disease in the United Kingdom. The Breast Specialty Group of the British Association of Surgical Oncology.
    Eur J Surg Oncol 1999 Feb;25(1):3-23

    Bone metastases can present to a number of different specialties and their successful management requires a coordinated approach with good liaison between the specialists. Patients who respond to systemic therapy for their metastases have a good chance of being alive at 3 years, and 20% will be alive at 5 years. This means that it is worth palliating these patients properly. With this in mind, the intention of this document is to try and improve the process of care for women with metastatic bone disease from breast cancer. These guidelines consider all aspects of care from diagnosis to assessment of response to treatment, and describe the Quality Objectives that should be addressed at each stage. The level of available evidence is indicated throughout the document where possible. In considering diagnosis, the guidelines emphasize the value of having a dedicated orthopaedic surgeon specifically linked to each Cancer Unit. The attachment of a dedicated orthopaedic surgeon will ensure that mechanical problems are correctly identified, and that actual or imminent fracture is correctly managed. The latter is particularly important as the management of pathological fractures is not the same as that of traumatic fractures. The orthopaedic surgeon should also act as the liaison between his/her own Unit and the tertiary spinal or neurosurgical centres as necessary. In addition, empowering the radiologist means that the diagnostic process can be accelerated and refined. The place of different investigations in diagnosis, including tumour markers, is discussed. The guidelines emphasize the need for a definitive diagnosis before treatment in the (rare) case of a solitary metastasis. The treatment section discusses orthopaedic management, radiotherapy and systemic treatments (endocrine therapy, chemotherapy and bisphosphonates). The guidelines emphasize the emergency nature of spinal cord compression, describing the need for fast access to assessment and for good liaison between specialists. It is essential that these are available and widely publicized to ensure effective management. The role of radiotherapy in both local pain relief and spinal cord compression is discussed, and various techniques are described. Endocrine therapy and chemotherapy are discussed in relation to the disease-free interval, performance status, extent and site of metastatic disease, and oestrogen receptor status. Specific chemotherapy regimes are not discussed as these are subject to change and local protocols should be followed. The increasing evidence behind the role of bisphosphonates is reviewed. With many unanswered questions about the long-term use of this group of drugs, the guidelines offer a scoring system for deciding which patients might benefit most from long-term bisphosphonate therapy. The guidelines describe the possible ways of assessing response to treatment and the difficulties that may be encountered, including a discussion of the role of tumour markers in assessment of response. A final section looks at palliative care principles in bone pain management, acknowledging the need for continuation of good care throughout the patient's journey, from diagnosis onwards. We very much hope these guidelines will stimulate individuals and institutions to improve the process of delivering care to this group of patients.