Lactate dehydrogenase B

A metabolic marker of response to neoadjuvant chemotherapy in breast cancer

Jennifer B. Dennison, Jennifer R. Molina, Shreya Mitra, Ana M. González-Angulo, Justin M. Balko, María G. Kuba, Melinda E. Sanders, Joseph A. Pinto, Henry L. Gómez, Carlos L. Arteaga, Robert E. Brown, Gordon B. Mills

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Abstract

Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. Experimental Design: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes - those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basallike subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006). Conclusions: Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy.

Original languageEnglish (US)
Pages (from-to)3703-3713
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2013

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Breast Neoplasms
Drug Therapy
Hormones
Cell Line
Neoplasms
Genes
Phenotype
lactate dehydrogenase 1
Recurrence
Research Design
Biomarkers
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dennison, J. B., Molina, J. R., Mitra, S., González-Angulo, A. M., Balko, J. M., Kuba, M. G., ... Mills, G. B. (2013). Lactate dehydrogenase B: A metabolic marker of response to neoadjuvant chemotherapy in breast cancer. Clinical Cancer Research, 19(13), 3703-3713. https://doi.org/10.1158/1078-0432.CCR-13-0623

Lactate dehydrogenase B : A metabolic marker of response to neoadjuvant chemotherapy in breast cancer. / Dennison, Jennifer B.; Molina, Jennifer R.; Mitra, Shreya; González-Angulo, Ana M.; Balko, Justin M.; Kuba, María G.; Sanders, Melinda E.; Pinto, Joseph A.; Gómez, Henry L.; Arteaga, Carlos L.; Brown, Robert E.; Mills, Gordon B.

In: Clinical Cancer Research, Vol. 19, No. 13, 01.07.2013, p. 3703-3713.

Research output: Contribution to journalArticle

Dennison, JB, Molina, JR, Mitra, S, González-Angulo, AM, Balko, JM, Kuba, MG, Sanders, ME, Pinto, JA, Gómez, HL, Arteaga, CL, Brown, RE & Mills, GB 2013, 'Lactate dehydrogenase B: A metabolic marker of response to neoadjuvant chemotherapy in breast cancer', Clinical Cancer Research, vol. 19, no. 13, pp. 3703-3713. https://doi.org/10.1158/1078-0432.CCR-13-0623
Dennison, Jennifer B. ; Molina, Jennifer R. ; Mitra, Shreya ; González-Angulo, Ana M. ; Balko, Justin M. ; Kuba, María G. ; Sanders, Melinda E. ; Pinto, Joseph A. ; Gómez, Henry L. ; Arteaga, Carlos L. ; Brown, Robert E. ; Mills, Gordon B. / Lactate dehydrogenase B : A metabolic marker of response to neoadjuvant chemotherapy in breast cancer. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 13. pp. 3703-3713.
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abstract = "Purpose: Although breast cancers are known to be molecularly heterogeneous, their metabolic phenotype is less well-understood and may predict response to chemotherapy. This study aimed to evaluate metabolic genes as individual predictive biomarkers in breast cancer. Experimental Design: mRNA microarray data from breast cancer cell lines were used to identify bimodal genes - those with highest potential for robust high/low classification in clinical assays. Metabolic function was evaluated in vitro for the highest scoring metabolic gene, lactate dehydrogenase B (LDHB). Its expression was associated with neoadjuvant chemotherapy response and relapse within clinical and PAM50-derived subtypes. Results: LDHB was highly expressed in cell lines with glycolytic, basal-like phenotypes. Stable knockdown of LDHB in cell lines reduced glycolytic dependence, linking LDHB expression directly to metabolic function. Using patient datasets, LDHB was highly expressed in basal-like cancers and could predict basallike subtype within clinical groups [OR = 21 for hormone receptor (HR)-positive/HER2-negative; OR = 10 for triple-negative]. Furthermore, high LDHB predicted pathologic complete response (pCR) to neoadjuvant chemotherapy for both HR-positive/HER2-negative (OR = 4.1, P < 0.001) and triple-negative (OR = 3.0, P = 0.003) cancers. For triple-negative tumors without pCR, high LDHB posttreatment also identified proliferative tumors with increased risk of recurrence (HR = 2.2, P = 0.006). Conclusions: Expression of LDHB predicted response to neoadjuvant chemotherapy within clinical subtypes independently of standard prognostic markers and PAM50 subtyping. These observations support prospective clinical evaluation of LDHB as a predictive marker of response for patients with breast cancer receiving neoadjuvant chemotherapy.",
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AU - González-Angulo, Ana M.

AU - Balko, Justin M.

AU - Kuba, María G.

AU - Sanders, Melinda E.

AU - Pinto, Joseph A.

AU - Gómez, Henry L.

AU - Arteaga, Carlos L.

AU - Brown, Robert E.

AU - Mills, Gordon B.

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