Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors

Norazizah Shafee, Christopher R. Smith, Shuanzeng Wei, Yoon Kim, Gordon Mills, Gabriel N. Hortobagyi, Eric J. Stanbridge, Eva Y.H.P. Lee

Research output: Contribution to journalArticle

227 Citations (Scopus)

Abstract

The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24-/lo and CD29 med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29hi24 med; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24 med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.

Original languageEnglish (US)
Pages (from-to)3243-3250
Number of pages8
JournalCancer Research
Volume68
Issue number9
DOIs
StatePublished - May 1 2008
Externally publishedYes

Fingerprint

Neoplastic Stem Cells
Cisplatin
Breast Neoplasms
Neoplasms
Platinum
Transplants
Population
Stem Cells
Clonal Evolution
Platinum Compounds
DNA Breaks
Doxorubicin
Breast
Recurrence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Shafee, N., Smith, C. R., Wei, S., Kim, Y., Mills, G., Hortobagyi, G. N., ... Lee, E. Y. H. P. (2008). Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Research, 68(9), 3243-3250. https://doi.org/10.1158/0008-5472.CAN-07-5480

Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. / Shafee, Norazizah; Smith, Christopher R.; Wei, Shuanzeng; Kim, Yoon; Mills, Gordon; Hortobagyi, Gabriel N.; Stanbridge, Eric J.; Lee, Eva Y.H.P.

In: Cancer Research, Vol. 68, No. 9, 01.05.2008, p. 3243-3250.

Research output: Contribution to journalArticle

Shafee, N, Smith, CR, Wei, S, Kim, Y, Mills, G, Hortobagyi, GN, Stanbridge, EJ & Lee, EYHP 2008, 'Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors', Cancer Research, vol. 68, no. 9, pp. 3243-3250. https://doi.org/10.1158/0008-5472.CAN-07-5480
Shafee, Norazizah ; Smith, Christopher R. ; Wei, Shuanzeng ; Kim, Yoon ; Mills, Gordon ; Hortobagyi, Gabriel N. ; Stanbridge, Eric J. ; Lee, Eva Y.H.P. / Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. In: Cancer Research. 2008 ; Vol. 68, No. 9. pp. 3243-3250.
@article{d411e85594ee4d3ab5e2f659bc13b9b9,
title = "Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors",
abstract = "The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80{\%} primary tumors (n = 8) show complete pathologic response. At greater dosages, 100{\%} show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8{\%} to 8.0{\%} (mean, 5.9{\%}) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24-/lo and CD29 med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6{\%} to 11.0{\%} (mean, 8.8{\%}) tumor cells are CD29hi24 med; these populations significantly increase to 16.5{\%} to 29.2{\%} (mean, 22.8{\%}; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24 med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.",
author = "Norazizah Shafee and Smith, {Christopher R.} and Shuanzeng Wei and Yoon Kim and Gordon Mills and Hortobagyi, {Gabriel N.} and Stanbridge, {Eric J.} and Lee, {Eva Y.H.P.}",
year = "2008",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-07-5480",
language = "English (US)",
volume = "68",
pages = "3243--3250",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors

AU - Shafee, Norazizah

AU - Smith, Christopher R.

AU - Wei, Shuanzeng

AU - Kim, Yoon

AU - Mills, Gordon

AU - Hortobagyi, Gabriel N.

AU - Stanbridge, Eric J.

AU - Lee, Eva Y.H.P.

PY - 2008/5/1

Y1 - 2008/5/1

N2 - The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24-/lo and CD29 med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29hi24 med; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24 med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.

AB - The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29hi24med, and these cells are tumorigenic, whereas CD29med24-/lo and CD29 med24hi cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29hi24 med; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29hi24 med populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.

UR - http://www.scopus.com/inward/record.url?scp=44849143103&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44849143103&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-07-5480

DO - 10.1158/0008-5472.CAN-07-5480

M3 - Article

VL - 68

SP - 3243

EP - 3250

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 9

ER -