Advancements in Human Breast Cancer Targeted Therapy and Immunotherapy

Abstract Background Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. Methods To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. Results We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. Conclusions Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

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Human Breast Cancer Tumor Models: Molecular Imaging of Drug Susceptibility and Dosing during HER2/neu-targeted Therapy

Radiology ◽

10.1148/radiol.2482071496 ◽

2008 ◽

Vol 248 (3) ◽

pp. 925-935 ◽

Cited By ~ 36

Author(s):

Michael S. Gee ◽

Rabi Upadhyay ◽

Henry Bergquist ◽

Herlen Alencar ◽

Fred Reynolds ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Molecular Imaging ◽

Human Breast Cancer ◽

Drug Susceptibility ◽

Human Breast ◽

Tumor Models ◽

Cancer Tumor

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Mechanisms of Disease: understanding resistance to HER2-targeted therapy in human breast cancer

Nature Clinical Practice Oncology ◽

10.1038/ncponc0509 ◽

2006 ◽

Vol 3 (5) ◽

pp. 269-280 ◽

Cited By ~ 548

Author(s):

Rita Nahta ◽

Dihua Yu ◽

Mien-Chie Hung ◽

Gabriel N Hortobagyi ◽

Francisco J Esteva

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Human Breast Cancer ◽

Human Breast ◽

Disease Understanding

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Targeted Therapy of Human Breast Cancer by 2-5A-Antisense Directed Against Telomerase RNA

10.21236/ada384610 ◽

1999 ◽

Author(s):

John K. Cowell

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Human Breast Cancer ◽

Telomerase Rna ◽

Human Breast

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Virus-Like Particles in a Human Breast Cancer: Structural Similarity to Previously Reported Particles

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072332 ◽

1973 ◽

Vol 31 ◽

pp. 378-379

Author(s):

G. Kasnic ◽

S. E. Stewart ◽

C. Urbanski

Keyword(s):

Breast Cancer ◽

Biological Activity ◽

Human Breast Cancer ◽

Osteogenic Sarcoma ◽

Human Tumor ◽

Structural Similarity ◽

Cell Tumor ◽

Human Breast ◽

Human Tumor Cell ◽

Type Particle

We have reported the maturation of an intracisternal A-type particle in murine plasma cell tumor cultures and three human tumor cell cultures (rhabdomyosarcoma, lung adenocarcinoma, and osteogenic sarcoma) after IUDR-DMSO activation. In all of these studies the A-type particle seems to develop into a form with an electron dense nucleoid, presumably mature, which is also intracisternal. A similar intracisternal A-type particle has been described in leukemic guinea pigs. Although no biological activity has yet been demonstrated for these particles, on morphologic grounds, and by the manner in which they develop within the cell, they may represent members of the same family of viruses.

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Further Ultrastructural Observations on Metastatic Nodules of Human Breast Cancer

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010010086x ◽

1968 ◽

Vol 26 ◽

pp. 224-225

Author(s):

John L. Swedo ◽

R. W. Talley ◽

John H. L. Watson

Keyword(s):

Breast Cancer ◽

Human Breast Cancer ◽

Estrogen Therapy ◽

Specimen Preparation ◽

Human Breast ◽

Autophagic Vacuoles ◽

Previous Communication ◽

Linear Profiles ◽

Metastatic Nodule

Since the report, which described the ultrastructure of a metastatic nodule of human breast cancer after estrogen therapy, additional ultrastructural observations, including some which are correlative with pertinent findings in the literature concerning mycoplasmas, have been recorded concerning the same subject. Specimen preparation was identical to that in.The mitochondria possessed few cristae, and were deteriorated and vacuolated. They often contained particulates and fibrous structures, sometimes arranged in spindle-shaped bundles, Fig. 1. Another apparent aberration was the occurrence, Fig. 2 (arrows) of linear profiles of what seems to be SER, which lie between layers of RER, and are often recognizably continuous with them.It was noted that the structure of the round bodies, interpreted as within autophagic vacuoles in the previous communication, and of vesicular bodies, described morphologically closely resembled those of some mycoplasmas. Specifically, they simulated or reflected the various stages of replication reported for mycoplasmas grown on solid nutrient. Based on this observation, they are referred to here as “mycoplasma-like” structures, in anticipation of confirmatory evidence from investigations now in progress.

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